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1. Associations between dyspnoea, coronary atherosclerosis, and cardiovascular outcomes: results from the long-term follow-up CONFIRM registry.

Author

van Rosendael, Alexander R, Bax, A Maxim, van den Hoogen, Inge J, Smit, Jeff M, Al'Aref, Subhi J, Achenbach, Stephan, Al-Mallah, Mouaz H, Andreini, Daniele, Berman, Daniel S, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, DeLago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Joerg, Kaufmann, Philipp A, Kim, Yong-Jin, Leipsic, Jonathon A, Maffei, Erica, Marques, Hugo, de Araújo Gonçalves, Pedro, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Villines, Todd C, Gransar, Heidi, Lu, Yao, Peña, Jessica M, Lin, Fay Y, Shaw, Leslee J, Narula, Jagat, Min, James K, and Bax, Jeroen J

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Atherosclerosis, Cardiovascular, Clinical Research, Biomedical Imaging, Heart Disease, Heart Disease - Coronary Heart Disease, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Aged, Coronary Angiography, Coronary Artery Disease, Dyspnea, Follow-Up Studies, Humans, Male, Middle Aged, Predictive Value of Tests, Prognosis, Prospective Studies, Registries, Risk Factors, coronary artery disease, coronary computed tomography angiography, dyspnoea, prognosis, Cardiovascular medicine and haematology
Abstract

AimsThe relationship between dyspnoea, coronary artery disease (CAD), and major cardiovascular events (MACE) is poorly understood. This study evaluated (i) the association of dyspnoea with the severity of anatomical CAD by coronary computed tomography angiography (CCTA) and (ii) to which extent CAD explains MACE in patients with dyspnoea.Methods and resultsFrom the international COronary CT Angiography EvaluatioN for Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 4425 patients (750 with dyspnoea) with suspected but without known CAD were included and prospectively followed for ≥5 years. First, the association of dyspnoea with CAD severity was assessed using logistic regression analysis. Second, the prognostic value of dyspnoea for MACE (myocardial infarction and death), and specifically, the interaction between dyspnoea and CAD severity was investigated using Cox proportional-hazard analysis. Mean patient age was 60.3 ± 11.9 years, 63% of patients were male and 592 MACE events occurred during a median follow-up duration of 5.4 (IQR 5.1-6.0) years. On uni- and multivariable analysis (adjusting for age, sex, body mass index, chest pain typicality, and risk factors), dyspnoea was associated with two- and three-vessel/left main (LM) obstructive CAD. The presence of dyspnoea increased the risk for MACE [hazard ratio (HR) 1.57, 95% confidence interval (CI): 1.29-1.90], which was modified after adjusting for clinical predictors and CAD severity (HR 1.26, 95% CI: 1.02-1.55). Conversely, when stratified by CAD severity, dyspnoea did not provide incremental prognostic value in one-, two-, or three-vessel/LM obstructive CAD, but dyspnoea did provide incremental prognostic value in non-obstructive CAD.ConclusionIn patients with suspected CAD, dyspnoea was independently associated with severe obstructive CAD on CCTA. The severity of obstructive CAD explained the elevated MACE rates in patients presenting with dyspnoea, but in patients with non-obstructive CAD, dyspnoea portended additional risk.

Published
2022

2. Effect of Intraoperative Dexmedetomidine on Recovery of Gastrointestinal Function After Abdominal Surgery in Older Adults

Author

Lu, Yao, Fang, Pan-Pan, Yu, Yong-Qi, Cheng, Xin-Qi, Feng, Xiao-Mei, Wong, Gordon Tin Chun, Maze, Mervyn, Liu, Xue-Sheng, Chen, Yong-Quan, Hu, Xian-Wen, Wang, Chun-Hui, Wei, Xin, Yuan, Hao, Xia, Xiao-Qiong, Wang, Sheng-Bin, Zhang, Qi, Chen, Jin-Bao, Zhan, Rui, Xu, Hui, Zhang, Qing, and Fan, Yinguang

Subjects
Clinical Trials and Supportive Activities, Patient Safety, Digestive Diseases, Aging, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, China, Dexmedetomidine, Digestive System Surgical Procedures, Double-Blind Method, Female, Gastrointestinal Tract, Humans, Hypnotics and Sedatives, Ileus, Intraoperative Care, Male, Middle Aged, Postoperative Complications, Time Factors, POGF Study Collaborators
Abstract

ImportancePostoperative ileus is common after abdominal surgery, and small clinical studies have reported that intraoperative administration of dexmedetomidine may be associated with improvements in postoperative gastrointestinal function. However, findings have been inconsistent and study samples have been small. Further examination of the effects of intraoperative dexmedetomidine on postoperative gastrointestinal function is needed.ObjectiveTo evaluate the effects of intraoperative intravenous dexmedetomidine vs placebo on postoperative gastrointestinal function among older patients undergoing abdominal surgery.Design, setting, and participantsThis multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at the First Affiliated Hospital of Anhui Medical University in Hefei, China (lead site), and 12 other tertiary hospitals in Anhui Province, China. A total of 808 participants aged 60 years or older who were scheduled to receive abdominal surgery with an expected surgical duration of 1 to 6 hours were enrolled. The study was conducted from August 21, 2018, to December 9, 2019.InterventionsDexmedetomidine infusion (a loading dose of 0.5 μg/kg over 15 minutes followed by a maintenance dose of 0.2 μg/kg per hour) or placebo infusion (normal saline) during surgery.Main outcomes and measuresThe primary outcome was time to first flatus. Secondary outcomes were postoperative gastrointestinal function measured by the I-FEED (intake, feeling nauseated, emesis, physical examination, and duration of symptoms) scoring system, time to first feces, time to first oral feeding, incidence of delirium, pain scores, sleep quality, postoperative nausea and vomiting, hospital costs, and hospital length of stay.ResultsAmong 808 patients enrolled, 404 were randomized to receive intraoperative dexmedetomidine, and 404 were randomized to receive placebo. In total, 133 patients (60 in the dexmedetomidine group and 73 in the placebo group) were excluded because of protocol deviations, and 675 patients (344 in the dexmedetomidine group and 331 in the placebo group; mean [SD] age, 70.2 [6.1] years; 445 men [65.9%]) were included in the per-protocol analysis. The dexmedetomidine group had a significantly shorter time to first flatus (median, 65 hours [IQR, 48-78 hours] vs 78 hours [62-93 hours], respectively; P

Published
2021

3. Priming COVID-19 salience increases prejudice and discriminatory intent against Asians and Hispanics

Author

Lu, Yao, Kaushal, Neeraj, Huang, Xiaoning, and Gaddis, S Michael

Subjects
Psychology, Social and Personality Psychology, Human Society, Behavioral and Social Science, Asian, Attitude, COVID-19, Hispanic or Latino, Humans, Intention, Minority Groups, Pandemics, Prejudice, Racism, United States, discrimination, race and ethnicity, prejudice
Abstract

Mounting reports in the media suggest that the COVID-19 pandemic has intensified prejudice and discrimination against racial/ethnic minorities, especially Asians. Existing research has focused on discrimination against Asians and is primarily based on self-reported incidents or nonrepresentative samples. We investigate the extent to which COVID-19 has fueled prejudice and discrimination against multiple racial/ethnic minority groups in the United States by examining nationally representative survey data with an embedded vignette experiment about roommate selection (collected in August 2020; n = 5,000). We find that priming COVID-19 salience has an immediate, statistically significant impact: compared to the control group, respondents in the treatment group exhibited increased prejudice and discriminatory intent against East Asian, South Asian, and Hispanic hypothetical room-seekers. The treatment effect is more pronounced in increasing extreme negative attitudes toward the three minority groups than decreasing extreme positive attitudes toward them. This is partly due to the treatment increasing the proportion of respondents who perceive these minority groups as extremely culturally incompatible (Asians and Hispanics) and extremely irresponsible (Asians). Sociopolitical factors did not moderate the treatment effects on attitudes toward Asians, but prior social contact with Hispanics mitigated prejudices against them. These findings suggest that COVID-19-fueled prejudice and discrimination have not been limited to East Asians but are part of a broader phenomenon that has affected Asians generally and Hispanics as well.

Published
2021

4. Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World

Author

Hirschfeld, Cole B, Shaw, Leslee J, Williams, Michelle C, Lahey, Ryan, Villines, Todd C, Dorbala, Sharmila, Choi, Andrew D, Shah, Nishant R, Bluemke, David A, Berman, Daniel S, Blankstein, Ron, Ferencik, Maros, Narula, Jagat, Winchester, David, Malkovskiy, Eli, Goebel, Benjamin, Randazzo, Michael J, Lopez-Mattei, Juan, Parwani, Purvi, Vitola, Joao V, Cerci, Rodrigo J, Better, Nathan, Raggi, Paolo, Lu, Bin, Sergienko, Vladimir, Sinitsyn, Valentin, Kudo, Takashi, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Cohen, Yosef A, Pascual, Thomas NB, Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, Einstein, Andrew J, Cerci, Rodrigo, Hinterleitner, Gerd, Lu, Yao, Morozova, Olga, Xu, Zhuoran, Cohen, Yosef, Randazzo, Michael, Choi, Andrew, Nasery, Mohammad Nawaz, Goda, Artan, Shirka, Ervina, Benlabgaa, Rabie, Bouyoucef, Salah, Medjahedi, Abdelkader, Nailli, Qais, Agolti, Mariela, Aguero, Roberto Nicolas, del Carmen Alak, Maria, Alberguina, Lucia Graciela, Arroñada, Guillermo, Astesiano, Andrea, Astesiano, Alfredo, Norton, Carolina Bas, Benteo, Pablo, Blanco, Juan, Bonelli, Juan Manuel, Bustos, Jose Javier, Cabrejas, Raul, Cachero, Jorge, Campisi, Roxana, Canderoli, Alejandro, Carames, Silvia, Carrascosa, Patrícia, Castro, Ricardo, Cendoya, Oscar, Cognigni, Luciano Martin, Collaud, Carlos, Cortes, Claudia, Courtis, Javier, Cragnolino, Daniel, Daicz, Mariana, De La Vega, Alejandro, De Maria, Silvia Teresa, Del Riego, Horacio, Dettori, Fernando, Deviggiano, Alejandro, and Dragonetti, Laura

Subjects
Heart Disease, Clinical Research, Health Services, Prevention, Aging, Cardiovascular, Good Health and Well Being, COVID-19, COVID-19 Testing, Humans, Pandemics, Predictive Value of Tests, SARS-CoV-2, United States, cardiovascular disease, cardiovascular imaging, coronavirus, diagnostic cardiovascular procedure, INCAPS-COVID Investigators Group, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

ObjectivesThis study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic.BackgroundThe COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality.MethodsData were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States.ResultsReductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p

Published
2021

5. Age- and sex-related features of atherosclerosis from coronary computed tomography angiography in patients prior to acute coronary syndrome: results from the ICONIC study

Author

Conte, Edoardo, Dwivedi, Aeshita, Mushtaq, Saima, Pontone, Gianluca, Lin, Fay Y, Hollenberg, Emma J, Lee, Sang-Eun, Bax, Jeroen, Cademartiri, Filippo, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, Feuchtner, Gudrun, Hadamitzky, Martin, Kim, Yong-Jin, Baggiano, Andrea, Leipsic, Jonathon, Maffei, Erica, Marques, Hugo, Plank, Fabian, Raff, Gilbert L, van Rosendael, Alexander R, Villines, Todd C, Weirich, Harald G, Al’Aref, Subhi J, Baskaran, Lohendran, Cho, Iksung, Danad, Ibrahim, Han, Donghee, Heo, Ran, Lee, Ji Hyun, Stuijfzand, Wijnand J, Gransar, Heidi, Lu, Yao, Sung, Ji Min, Park, Hyung-Bok, Al-Mallah, Mouaz H, de Araújo Gonçalves, Pedro, Berman, Daniel S, Budoff, Matthew J, Samady, Habib, Shaw, Leslee J, Stone, Peter H, Virmani, Renu, Narula, Jagat, Min, James K, Chang, Hyuk-Jae, and Andreini, Daniele

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Heart Disease, Atherosclerosis, Biomedical Imaging, Aging, Clinical Research, Heart Disease - Coronary Heart Disease, Cardiovascular, Acute Coronary Syndrome, Aged, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Female, Humans, Male, Plaque, Atherosclerotic, atherosclerosis, gender medicine, cardiac CT, high-risk plaque features, CCTA, Cardiovascular medicine and haematology
Abstract

AimsAlthough there is increasing evidence supporting coronary atherosclerosis evaluation by coronary computed tomography angiography (CCTA), no data are available on age and sex differences for quantitative plaque features. The aim of this study was to investigate sex and age differences in both qualitative and quantitative atherosclerotic features from CCTA prior to acute coronary syndrome (ACS).Methods and resultsWithin the ICONIC study, in which 234 patients with subsequent ACS were propensity matched 1:1 with 234 non-event controls, our current subanalysis included only the ACS cases. Both qualitative and quantitative advance plaque analysis by CCTA were performed by a core laboratory. In 129 cases, culprit lesions identified by invasive coronary angiography at the time of ACS were co-registered to baseline CCTA precursor lesions. The study population was then divided into subgroups according to sex and age (

Published
2021

6. International Impact of COVID-19 on the Diagnosis of Heart Disease

Author

Einstein, Andrew J, Shaw, Leslee J, Hirschfeld, Cole, Williams, Michelle C, Villines, Todd C, Better, Nathan, Vitola, Joao V, Cerci, Rodrigo, Dorbala, Sharmila, Raggi, Paolo, Choi, Andrew D, Lu, Bin, Sinitsyn, Valentin, Sergienko, Vladimir, Kudo, Takashi, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Campisi, Roxana, Milan, Elisa, Louw, Lizette, Allam, Adel H, Bhatia, Mona, Malkovskiy, Eli, Goebel, Benjamin, Cohen, Yosef, Randazzo, Michael, Narula, Jagat, Pascual, Thomas NB, Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, Hinterleitner, Gerd, Lu, Yao, Morozova, Olga, Xu, Zhuoran, Lopez-Mattei, Juan, Parwani, Purvi, Nasery, Mohammad Nawaz, Goda, Artan, Shirka, Ervina, Benlabgaa, Rabie, Bouyoucef, Salah, Medjahedi, Abdelkader, Nailli, Qais, Agolti, Mariela, Aguero, Roberto Nicolas, del Carmen Alak, Maria, Alberguina, Lucia Graciela, Arroñada, Guillermo, Astesiano, Andrea, Astesiano, Alfredo, Norton, Carolina Bas, Benteo, Pablo, Blanco, Juan, Bonelli, Juan Manuel, Bustos, Jose Javier, Cabrejas, Raul, Cachero, Jorge, Canderoli, Alejandro, Carames, Silvia, Carrascosa, Patrícia, Castro, Ricardo, Cendoya, Oscar, Cognigni, Luciano Martin, Collaud, Carlos, Cortes, Claudia, Courtis, Javier, Cragnolino, Daniel, Daicz, Mariana, De La Vega, Alejandro, De Maria, Silvia Teresa, Del Riego, Horacio, Dettori, Fernando, Deviggiano, Alejandro, Dragonetti, Laura, Embon, Mario, Enriquez, Ruben Emilio, Ensinas, Jorge, Faccio, Fernando, Facello, Adolfo, Garofalo, Diego, Geronazzo, Ricardo, Gonza, Natalia, Gutierrez, Lucas, Guzzo, Miguel Angel, Hasbani, Victor, Huerin, Melina, Jäger, Victor, Lewkowicz, Julio Manuel, De Munaín, Maria Nieves A López, Lotti, Jose Maria, Marquez, Alejandra, Masoli, Osvaldo, Mastrovito, Edgardo, Mayoraz, Matias, Melado, Graciela Eva, Mele, Anibal, Merani, Maria Fernanda, Meretta, Alejandro Horacio, and Molteni, Susana

Subjects
Heart Disease, Biomedical Imaging, Clinical Research, Cardiovascular, Heart Disease - Coronary Heart Disease, Good Health and Well Being, COVID-19, Diagnostic Techniques, Cardiovascular, Global Health, Health Care Surveys, Heart Diseases, Humans, International Agencies, the, INCAPS COVID Investigators Group, cardiac testing, cardiovascular disease, coronavirus, global health, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has adversely affected diagnosis and treatment of noncommunicable diseases. Its effects on delivery of diagnostic care for cardiovascular disease, which remains the leading cause of death worldwide, have not been quantified.ObjectivesThe study sought to assess COVID-19's impact on global cardiovascular diagnostic procedural volumes and safety practices.MethodsThe International Atomic Energy Agency conducted a worldwide survey assessing alterations in cardiovascular procedure volumes and safety practices resulting from COVID-19. Noninvasive and invasive cardiac testing volumes were obtained from participating sites for March and April 2020 and compared with those from March 2019. Availability of personal protective equipment and pandemic-related testing practice changes were ascertained.ResultsSurveys were submitted from 909 inpatient and outpatient centers performing cardiac diagnostic procedures, in 108 countries. Procedure volumes decreased 42% from March 2019 to March 2020, and 64% from March 2019 to April 2020. Transthoracic echocardiography decreased by 59%, transesophageal echocardiography 76%, and stress tests 78%, which varied between stress modalities. Coronary angiography (invasive or computed tomography) decreased 55% (p

Published
2021

7. A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Regorafenib Versus Placebo in Advanced/Metastatic, Treatment-Refractory Liposarcoma: Results from the SARC024 Study.

Author

Riedel, Richard F, Ballman, Karla V, Lu, Yao, Attia, Steven, Loggers, Elizabeth T, Ganjoo, Kristen N, Livingston, Michael B, Chow, Warren, Wright, Jennifer, Ward, John H, Rushing, Daniel, Okuno, Scott H, Reed, Damon R, Liebner, David A, Keedy, Vicki L, Mascarenhas, Leo, Davis, Lara E, Ryan, Christopher, Reinke, Denise K, and Maki, Robert G

Subjects
Humans, Liposarcoma, Phenylurea Compounds, Pyridines, Protein Kinase Inhibitors, Treatment Outcome, Double-Blind Method, Adult, Aged, Middle Aged, Female, Male, Clinical Research, Clinical Trials and Supportive Activities, Cancer, 6.1 Pharmaceuticals, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

Lessons learnedThe results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist.BackgroundRegorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients.MethodsPatients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1.ResultsForty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib.ConclusionRegorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

Published
2020

8. A Boosted Ensemble Algorithm for Determination of Plaque Stability in High-Risk Patients on Coronary CTA

Author

Al'Aref, Subhi J, Singh, Gurpreet, Choi, Jeong W, Xu, Zhuoran, Maliakal, Gabriel, van Rosendael, Alexander R, Lee, Benjamin C, Fatima, Zahra, Andreini, Daniele, Bax, Jeroen J, Cademartiri, Filippo, Chinnaiyan, Kavitha, Chow, Benjamin JW, Conte, Edoardo, Cury, Ricardo C, Feuchtner, Gudruf, Hadamitzky, Martin, Kim, Yong-Jin, Lee, Sang-Eun, Leipsic, Jonathon A, Maffei, Erica, Marques, Hugo, Plank, Fabian, Pontone, Gianluca, Raff, Gilbert L, Villines, Todd C, Weirich, Harald G, Cho, Iksung, Danad, Ibrahim, Han, Donghee, Heo, Ran, Lee, Ji Hyun, Rizvi, Asim, Stuijfzand, Wijnand J, Gransar, Heidi, Lu, Yao, Sung, Ji Min, Park, Hyung-Bok, Berman, Daniel S, Budoff, Matthew J, Samady, Habib, Stone, Peter H, Virmani, Renu, Narula, Jagat, Chang, Hyuk-Jae, Lin, Fay Y, Baskaran, Lohendran, Shaw, Leslee J, and Min, James K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Cardiovascular, Clinical Research, Heart Disease, Heart Disease - Coronary Heart Disease, Atherosclerosis, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Algorithms, Case-Control Studies, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Coronary Stenosis, Humans, Plaque, Atherosclerotic, Predictive Value of Tests, Severity of Illness Index, acute coronary syndrome, coronary computed tomography angiography, diameter stenosis, machine learning, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

ObjectivesThis study sought to identify culprit lesion (CL) precursors among acute coronary syndrome (ACS) patients based on qualitative and quantitative computed tomography-based plaque characteristics.BackgroundCoronary computed tomography angiography (CTA) has been validated for patient-level prediction of ACS. However, the applicability of coronary CTA to CL assessment is not known.MethodsUtilizing the ICONIC (Incident COroNary Syndromes Identified by Computed Tomography) study, a nested case-control study of 468 patients with baseline coronary CTA, the study included ACS patients with invasive coronary angiography-adjudicated CLs that could be aligned to CL precursors on baseline coronary CTA. Separate blinded core laboratories adjudicated CLs and performed atherosclerotic plaque evaluation. Thereafter, the study used a boosted ensemble algorithm (XGBoost) to develop a predictive model of CLs. Data were randomly split into a training set (80%) and a test set (20%). The area under the receiver-operating characteristic curve of this model was compared with that of diameter stenosis (model 1), high-risk plaque features (model 2), and lesion-level features of CL precursors from the ICONIC study (model 3). Thereafter, the machine learning (ML) model was applied to 234 non-ACS patients with 864 lesions to determine model performance for CL exclusion.ResultsCL precursors were identified by both coronary angiography and baseline coronary CTA in 124 of 234 (53.0%) patients, with a total of 582 lesions (containing 124 CLs) included in the analysis. The ML model demonstrated significantly higher area under the receiver-operating characteristic curve for discriminating CL precursors (0.774; 95% confidence interval [CI]: 0.758 to 0.790) compared with model 1 (0.599; 95% CI: 0.599 to 0.599; p

Published
2020

9. Non-obstructive high-risk plaques increase the risk of future culprit lesions comparable to obstructive plaques without high-risk features: the ICONIC study

Author

Ferraro, Richard A, van Rosendael, Alexander R, Lu, Yao, Andreini, Daniele, Al-Mallah, Mouaz H, Cademartiri, Filippo, Chinnaiyan, Kavitha, Chow, Benjamin JW, Conte, Edoardo, Cury, Ricardo C, Feuchtner, Gudrun, de Araújo Gonçalves, Pedro, Hadamitzky, Martin, Kim, Yong-Jin, Leipsic, Jonathon, Maffei, Erica, Marques, Hugo, Plank, Fabian, Pontone, Gianluca, Raff, Gilbert L, Villines, Todd C, Lee, Sang-Eun, Al’Aref, Subhi J, Baskaran, Lohendran, Cho, Iksung, Danad, Ibrahim, Gransar, Heidi, Budoff, Matthew J, Samady, Habib, Stone, Peter H, Virmani, Renu, Narula, Jagat, Berman, Daniel S, Chang, Hyuk-Jae, Bax, Jeroen J, Min, James K, Shaw, Leslee J, and Lin, Fay Y

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Research, Heart Disease - Coronary Heart Disease, Heart Disease, Atherosclerosis, Cardiovascular, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Acute Coronary Syndrome, Aged, Case-Control Studies, Coronary Angiography, Coronary Artery Disease, Coronary Vessels, Female, Humans, Male, Middle Aged, Plaque, Atherosclerotic, Predictive Value of Tests, Retrospective Studies, Risk Factors, Coronary computed tomographic angiography, coronary artery disease, myocardial infarction, Cardiovascular medicine and haematology
Abstract

AimsHigh-risk plaque (HRP) and non-obstructive coronary artery disease independently predict adverse events, but their importance to future culprit lesions has not been resolved. We sought to determine in patients prior to confirmed acute coronary syndrome (ACS) the association between lesion percent diameter stenosis (%DS), and the absolute number and prevalence of HRP. The secondary objective was to examine the relative importance of non-obstructive HRP in future culprit lesions.Methods and resultsWithin the ICONIC study, a nested case-control study of patients undergoing coronary computed tomographic angiography (coronary CT), we included ACS cases with culprit lesions confirmed by invasive coronary angiography and coregistered to baseline coronary CT. Quantitative CT was used to evaluate obstructive (≥50%) and non-obstructive (

Published
2020

10. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

Author

Giri, Veda N, Knudsen, Karen E, Kelly, William K, Cheng, Heather H, Cooney, Kathleen A, Cookson, Michael S, Dahut, William, Weissman, Scott, Soule, Howard R, Petrylak, Daniel P, Dicker, Adam P, AlDubayan, Saud H, Toland, Amanda E, Pritchard, Colin C, Pettaway, Curtis A, Daly, Mary B, Mohler, James L, Parsons, J Kellogg, Carroll, Peter R, Pilarski, Robert, Blanco, Amie, Woodson, Ashley, Rahm, Alanna, Taplin, Mary-Ellen, Polascik, Thomas J, Helfand, Brian T, Hyatt, Colette, Morgans, Alicia K, Feng, Felix, Mullane, Michael, Powers, Jacqueline, Concepcion, Raoul, Lin, Daniel W, Wender, Richard, Mark, James Ryan, Costello, Anthony, Burnett, Arthur L, Sartor, Oliver, Isaacs, William B, Xu, Jianfeng, Weitzel, Jeffrey, Andriole, Gerald L, Beltran, Himisha, Briganti, Alberto, Byrne, Lindsey, Calvaresi, Anne, Chandrasekar, Thenappan, Chen, David YT, Den, Robert B, Dobi, Albert, Crawford, E David, Eastham, James, Eggener, Scott, Freedman, Matthew L, Garnick, Marc, Gomella, Patrick T, Handley, Nathan, Hurwitz, Mark D, Izes, Joseph, Karnes, R Jeffrey, Lallas, Costas, Languino, Lucia, Loeb, Stacy, Lopez, Ana Maria, Loughlin, Kevin R, Lu-Yao, Grace, Malkowicz, S Bruce, Mann, Mark, Mille, Patrick, Miner, Martin M, Morgan, Todd, Moreno, Jose, Mucci, Lorelei, Myers, Ronald E, Nielsen, Sarah M, O'Neil, Brock, Pinover, Wayne, Pinto, Peter, Poage, Wendy, Raj, Ganesh V, Rebbeck, Timothy R, Ryan, Charles, Sandler, Howard, Schiewer, Matthew, Scott, E Michael D, Szymaniak, Brittany, Tester, William, Trabulsi, Edouard J, Vapiwala, Neha, Yu, Evan Y, Zeigler-Johnson, Charnita, and Gomella, Leonard G

Subjects
Biotechnology, Aging, Genetics, Prevention, Clinical Research, Cancer, Prostate Cancer, Genetic Testing, Urologic Diseases, Health Services, Good Health and Well Being, Germ-Line Mutation, History, 20th Century, Humans, Male, Prostatic Neoplasms, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeGermline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.MethodsA multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).ResultsLarge germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.ConclusionThis multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Published
2020

11. Clinical risk factors and atherosclerotic plaque extent to define risk for major events in patients without obstructive coronary artery disease: the long-term coronary computed tomography angiography CONFIRM registry

Author

van Rosendael, Alexander R, Bax, A Maxim, Smit, Jeff M, van den Hoogen, Inge J, Ma, Xiaoyue, Al’Aref, Subhi, Achenbach, Stephan, Al-Mallah, Mouaz H, Andreini, Daniele, Berman, Daniel S, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, DeLago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Joerg, Kaufmann, Philipp A, Kim, Yong-Jin, Leipsic, Jonathon A, Maffei, Erica, Marques, Hugo, de Araújo Gonçalves, Pedro, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Villines, Todd C, Gransar, Heidi, Lu, Yao, Peña, Jessica M, Lin, Fay Y, Shaw, Leslee J, Min, James K, and Bax, Jeroen J

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Heart Disease - Coronary Heart Disease, Aging, Patient Safety, Cardiovascular, Clinical Research, Atherosclerosis, Biomedical Imaging, Heart Disease, Prevention, Diabetes, 2.1 Biological and endogenous factors, Aetiology, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Aged, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Female, Humans, Male, Middle Aged, Plaque, Atherosclerotic, Predictive Value of Tests, Prognosis, Registries, Risk Factors, coronary computed tomography angiography, risk stratification, atherosclerosis, imaging, preventive cardiology, Cardiovascular medicine and haematology
Abstract

AimsIn patients without obstructive coronary artery disease (CAD), we examined the prognostic value of risk factors and atherosclerotic extent.Methods and resultsPatients from the long-term CONFIRM registry without prior CAD and without obstructive (≥50%) stenosis were included. Within the groups of normal coronary computed tomography angiography (CCTA) (N = 1849) and non-obstructive CAD (N = 1698), the prognostic value of traditional clinical risk factors and atherosclerotic extent (segment involvement score, SIS) was assessed with Cox models. Major adverse cardiac events (MACE) were defined as all-cause mortality, non-fatal myocardial infarction, or late revascularization. In total, 3547 patients were included (age 57.9 ± 12.1 years, 57.8% male), experiencing 460 MACE during 5.4 years of follow-up. Age, body mass index, hypertension, and diabetes were the clinical variables associated with increased MACE risk, but the magnitude of risk was higher for CCTA defined atherosclerotic extent; adjusted hazard ratio (HR) for SIS >5 was 3.4 (95% confidence interval [CI] 2.3-4.9) while HR for diabetes and hypertension were 1.7 (95% CI 1.3-2.2) and 1.4 (95% CI 1.1-1.7), respectively. Exclusion of revascularization as endpoint did not modify the results. In normal CCTA, presence of ≥1 traditional risk factors did not worsen prognosis (log-rank P = 0.248), while it did in non-obstructive CAD (log-rank P = 0.025). Adjusted for SIS, hypertension and diabetes predicted MACE risk in non-obstructive CAD, while diabetes did not increase risk in absence of CAD (P-interaction = 0.004).ConclusionAmong patients without obstructive CAD, the extent of CAD provides more prognostic information for MACE than traditional cardiovascular risk factors. An interaction was observed between risk factors and CAD burden, suggesting synergistic effects of both.

Published
2020

12. Coronary atherosclerosis scoring with semiquantitative CCTA risk scores for prediction of major adverse cardiac events: Propensity score-based analysis of diabetic and non-diabetic patients

Author

van den Hoogen, Inge J, van Rosendael, Alexander R, Lin, Fay Y, Lu, Yao, Dimitriu-Leen, Aukelien C, Smit, Jeff M, Scholte, Arthur JHA, Achenbach, Stephan, Al-Mallah, Mouaz H, Andreini, Daniele, Berman, Daniel S, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, DeLago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Joerg, Kaufmann, Philipp A, Kim, Yong-Jin, Leipsic, Jonathon A, Maffei, Erica, Marques, Hugo, de Araújo Gonçalves, Pedro, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Villines, Todd C, Gransar, Heidi, Jones, Erica C, Peña, Jessica M, Shaw, Leslee J, Min, James K, and Bax, Jeroen J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Patient Safety, Prevention, Diabetes, Heart Disease, Cardiovascular, Heart Disease - Coronary Heart Disease, Clinical Research, Atherosclerosis, Biomedical Imaging, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Aged, Case-Control Studies, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Coronary Stenosis, Diabetes Mellitus, Disease Progression, Female, Humans, Male, Middle Aged, Multidetector Computed Tomography, Predictive Value of Tests, Prognosis, Propensity Score, Registries, Risk Assessment, Risk Factors, Severity of Illness Index, Computed tomography, Diabetes mellitus, Prognostic application, Risk stratification, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Applied computing
Abstract

AimsWe aimed to compare semiquantitative coronary computed tomography angiography (CCTA) risk scores - which score presence, extent, composition, stenosis and/or location of coronary artery disease (CAD) - and their prognostic value between patients with and without diabetes mellitus (DM). Risk scores derived from general chest-pain populations are often challenging to apply in DM patients, because of numerous confounders.MethodsOut of a combined cohort from the Leiden University Medical Center and the CONFIRM registry with 5-year follow-up data, we performed a secondary analysis in diabetic patients with suspected CAD who were clinically referred for CCTA. A total of 732 DM patients was 1:1 propensity-matched with 732 non-DM patients by age, sex and cardiovascular risk factors. A subset of 7 semiquantitative CCTA risk scores was compared between groups: 1) any stenosis ≥50%, 2) any stenosis ≥70%, 3) stenosis-severity component of the coronary artery disease-reporting and data system (CAD-RADS), 4) segment involvement score (SIS), 5) segment stenosis score (SSS), 6) CT-adapted Leaman score (CT-LeSc), and 7) Leiden CCTA risk score. Cox-regression analysis was performed to assess the association between the scores and the primary endpoint of all-cause death and non-fatal myocardial infarction. Also, area under the receiver-operating characteristics curves were compared to evaluate discriminatory ability.ResultsA total of 1,464 DM and non-DM patients (mean age 58 ± 12 years, 40% women) underwent CCTA and 155 (11%) events were documented after median follow-up of 5.1 years. In DM patients, the 7 semiquantitative CCTA risk scores were significantly more prevalent or higher as compared to non-DM patients (p ≤ 0.022). All scores were independently associated with the primary endpoint in both patients with and without DM (p ≤ 0.020), with non-significant interaction between the scores and diabetes (interaction p ≥ 0.109). Discriminatory ability of the Leiden CCTA risk score in DM patients was significantly better than any stenosis ≥50% and ≥70% (p = 0.003 and p = 0.007, respectively), but comparable to the CAD-RADS, SIS, SSS and CT-LeSc that also focus on the extent of CAD (p ≥ 0.265).ConclusionCoronary atherosclerosis scoring with semiquantitative CCTA risk scores incorporating the total extent of CAD discriminate major adverse cardiac events well, and might be useful for risk stratification of patients with DM beyond the binary evaluation of obstructive stenosis alone.

Published
2020

13. Increased long-term mortality in women with high left ventricular ejection fraction: data from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) long-term registry

Author

Gebhard, Catherine, Maredziak, Monika, Messerli, Michael, Buechel, Ronny R, Lin, Fay, Gransar, Heidi, Achenbach, Stephan, Al-Mallah, Mouaz H, Andreini, Daniele, Bax, Jeroen J, Berman, Daniel S, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, DeLago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Joerg, Kim, Yong-Jin, Leipsic, Jonathon, Maffei, Erica, Marques, Hugo, de Araújo Gonçalves, Pedro, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Shaw, Leslee J, Villines, Todd C, Lu, Yao, Jones, Erica C, Peña, Jessica M, Min, James K, and Kaufmann, Philipp A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Aging, Cardiovascular, Heart Disease, Clinical Trials and Supportive Activities, Biomedical Imaging, Clinical Research, Atherosclerosis, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Good Health and Well Being, Aged, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Female, Humans, Male, Middle Aged, Prognosis, Prospective Studies, Registries, Severity of Illness Index, Stroke Volume, Ventricular Function, Left, women, gender, coronary computed tomography angiography, left ventricular ejection fraction, cardiovascular, cardiovascular, Cardiovascular medicine and haematology
Abstract

AimsThere are significant sex-specific differences in left ventricular ejection fraction (LVEF), with a higher LVEF being observed in women. We sought to assess the clinical relevance of an increased LVEF in women and men.Methods and resultsA total of 4632 patients from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry (44.8% women; mean age 58.7 ± 13.2 years in men and 59.5 ± 13.3 years in women, P = 0.05), in whom LVEF was measured by cardiac computed tomography, were categorized according to LVEF (low 65%). The prevalence of high LVEF was similar in both sexes (33.5% in women and 32.5% in men, P = 0.46). After 6 years of follow-up, no difference in mortality was observed in patients with high LVEF in the overall cohort (P = 0.41). When data were stratified by sex, women with high LVEF died more often from any cause as compared to women with normal LVEF (8.6% vs. 7.1%, log rank P = 0.032), while an opposite trend was observed in men (5.8% vs. 6.8% in normal LVEF, log rank P = 0.89). Accordingly, a first order interaction term of male sex and high LVEF was significant (hazard ratios 0.63, 95% confidence intervals 0.41-0.98, P = 0.043) in a Cox regression model of all-cause mortality adjusted for age, cardiovascular risk factors, and severity of coronary artery disease (CAD).ConclusionIncreased LVEF is highly prevalent in patients referred for evaluation of CAD and is associated with an increased risk of death in women, but not in men. Differentiating between normal and hyperdynamic left ventricles might improve risk stratification in women with CAD.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT01443637.

Published
2020

14. Machine learning of clinical variables and coronary artery calcium scoring for the prediction of obstructive coronary artery disease on coronary computed tomography angiography: analysis from the CONFIRM registry.

Author

Al'Aref, Subhi J, Maliakal, Gabriel, Singh, Gurpreet, van Rosendael, Alexander R, Ma, Xiaoyue, Xu, Zhuoran, Alawamlh, Omar Al Hussein, Lee, Benjamin, Pandey, Mohit, Achenbach, Stephan, Al-Mallah, Mouaz H, Andreini, Daniele, Bax, Jeroen J, Berman, Daniel S, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, DeLago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Joerg, Kaufmann, Philipp A, Kim, Yong-Jin, Leipsic, Jonathon A, Maffei, Erica, Marques, Hugo, Gonçalves, Pedro de Araújo, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Villines, Todd C, Gransar, Heidi, Lu, Yao, Jones, Erica C, Peña, Jessica M, Lin, Fay Y, Min, James K, and Shaw, Leslee J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Biomedical Imaging, Clinical Research, Atherosclerosis, Cardiovascular, Heart Disease, Heart Disease - Coronary Heart Disease, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Calcium, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Coronary Vessels, Female, Humans, Machine Learning, Male, Middle Aged, Multidetector Computed Tomography, Predictive Value of Tests, Prospective Studies, ROC Curve, Registries, Coronary artery disease, Coronary artery calcium score, Machine learning, Coronary computed tomography angiography, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

AimsSymptom-based pretest probability scores that estimate the likelihood of obstructive coronary artery disease (CAD) in stable chest pain have moderate accuracy. We sought to develop a machine learning (ML) model, utilizing clinical factors and the coronary artery calcium score (CACS), to predict the presence of obstructive CAD on coronary computed tomography angiography (CCTA).Methods and resultsThe study screened 35 281 participants enrolled in the CONFIRM registry, who underwent ≥64 detector row CCTA evaluation because of either suspected or previously established CAD. A boosted ensemble algorithm (XGBoost) was used, with data split into a training set (80%) on which 10-fold cross-validation was done and a test set (20%). Performance was assessed of the (1) ML model (using 25 clinical and demographic features), (2) ML + CACS, (3) CAD consortium clinical score, (4) CAD consortium clinical score + CACS, and (5) updated Diamond-Forrester (UDF) score. The study population comprised of 13 054 patients, of whom 2380 (18.2%) had obstructive CAD (≥50% stenosis). Machine learning with CACS produced the best performance [area under the curve (AUC) of 0.881] compared with ML alone (AUC of 0.773), CAD consortium clinical score (AUC of 0.734), and with CACS (AUC of 0.866) and UDF (AUC of 0.682), P

Published
2020

15. Long-term prognostic utility of computed tomography coronary angiography in older populations.

Author

Gnanenthiran, Sonali R, Naoum, Christopher, Leipsic, Jonathon A, Achenbach, Stephan, Al-Mallah, Mouaz H, Andreini, Daniele, Bax, Jeroen J, Berman, Daniel S, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, DeLago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Joerg, Kaufman, Philipp A, Kim, Yong-Jin, Maffei, Erica, Marques, Hugo, de Araújo Gonçalves, Pedro, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Shaw, Leslee J, Villines, Todd C, Gransar, Heidi, Lu, Yao, Jones, Erica C, Peña, Jessica M, Lin, Fay Y, Kritharides, Leonard, and Min, James K

Subjects
Prevention, Biomedical Imaging, Heart Disease - Coronary Heart Disease, Aging, Cardiovascular, Clinical Research, Atherosclerosis, Heart Disease, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Age Factors, Aged, Aged, 80 and over, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Prognosis, Prospective Studies, Registries, coronary computed tomography angiography, age, older populations, mortality, major adverse cardiovascular events, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology
Abstract

AimsThe long-term prognostic value of coronary computed tomography angiography (CCTA)-identified coronary artery disease (CAD) has not been evaluated in elderly patients (≥70 years). We compared the ability of coronary CCTA to predict 5-year mortality in older vs. younger populations.Methods and resultsFrom the prospective CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, we analysed CCTA results according to age 50%); (ii) segment involvement score (SIS): number of segments with plaque. Cox-proportional hazard models assessed the relationship between CCTA findings and time to mortality. At a mean 5.6 ± 1.1 year follow-up, CCTA-identified CAD predicted increased mortality compared with patients with a normal CCTA in both

Published
2019

16. A cross-sectional survey of coronary plaque composition in individuals on non-statin lipid lowering drug therapies and undergoing coronary computed tomography angiography

Author

Al'Aref, Subhi J, Su, Amanda, Gransar, Heidi, van Rosendael, Alexander R, Rizvi, Asim, Berman, Daniel S, Callister, Tracy Q, DeLago, Augustin, Hadamitzky, Martin, Hausleiter, Joerg, Al-Mallah, Mouaz H, Budoff, Matthew J, Kaufmann, Philipp A, Raff, Gilbert L, Chinnaiyan, Kavitha, Cademartiri, Filippo, Maffei, Erica, Villines, Todd C, Kim, Yong-Jin, Leipsic, Jonathon, Feuchtner, Gudrun, Pontone, Gianluca, Andreini, Daniele, Marques, Hugo, de Araújo Gonçalves, Pedro, Rubinshtein, Ronen, Achenbach, Stephan, Chang, Hyuk-Jae, Chow, Benjamin JW, Cury, Ricardo, Lu, Yao, Bax, Jeroen J, Jones, Erica C, Peña, Jessica M, Shaw, Leslee J, Min, James K, and Lin, Fay Y

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Heart Disease - Coronary Heart Disease, Atherosclerosis, Cardiovascular, Heart Disease, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Aetiology, 2.1 Biological and endogenous factors, Evaluation of treatments and therapeutic interventions, Aged, Asia, Biomarkers, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Coronary Stenosis, Coronary Vessels, Cross-Sectional Studies, Drug Therapy, Combination, Dyslipidemias, Europe, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypolipidemic Agents, Lipids, Male, Middle Aged, North America, Plaque, Atherosclerotic, Predictive Value of Tests, Prevalence, Registries, Risk Factors, Coronary computed tomography angiography, Coronary plaque composition, Non-statin therapy, Ezetimibe, Fibrate, Niacin, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Applied computing
Abstract

IntroductionNon-statin therapy (NST) is used as second-line treatment when statin monotherapy is inadequate or poorly tolerated.ObjectiveTo determine the association of NST with plaque composition, alone or in combination with statins, in patients undergoing coronary computed tomography angiography (coronary CTA).MethodsFrom the multicenter CONFIRM registry, we analyzed individuals who underwent coronary CTA with known lipid-lowering therapy status and without prior coronary artery disease at baseline. We created a propensity score for being on NST, followed by stepwise multivariate linear regression, adjusting for the propensity score as well as risk factors, to determine the association between NST and the number of coronary artery segments with each plaque type (non-calcified (NCP), partially calcified (PCP) or calcified (CP)) and segment stenosis score (SSS).ResultsOf the 27,125 subjects in CONFIRM, 4,945 met the inclusion criteria; 371 (7.5%) took NST. At baseline, patients on NST had more prevalent risk factors and were more likely to be on concomitant cardiac medications. After multivariate and propensity score adjustment, NST was not associated with plaque composition: NCP (0.07 increase, 95% CI: -0.05, 0.20; p = 0.26), PCP (0.10 increase, 95% CI: -0.10, 0.31; p = 0.33), CP (0.18 increase, 95% CI: -0.10, 0.46; p = 0.21) or SSS (0.45 increase, 95% CI: -0.02,0.93; p = 0.06). The absence of an effect of NST on plaque type was not modified by statin use (p for interaction > 0.05 for all).ConclusionIn this cross-sectional study, non-statin therapy was not associated with differences in plaque composition as assessed by coronary CTA.

Published
2019

17. Coronary Atherosclerotic Precursors of Acute Coronary Syndromes

Author

Chang, Hyuk-Jae, Lin, Fay Y, Lee, Sang-Eun, Andreini, Daniele, Bax, Jeroen, Cademartiri, Filippo, Chinnaiyan, Kavitha, Chow, Benjamin JW, Conte, Edoardo, Cury, Ricardo C, Feuchtner, Gudrun, Hadamitzky, Martin, Kim, Yong-Jin, Leipsic, Jonathon, Maffei, Erica, Marques, Hugo, Plank, Fabian, Pontone, Gianluca, Raff, Gilbert L, van Rosendael, Alexander R, Villines, Todd C, Weirich, Harald G, Al’Aref, Subhi J, Baskaran, Lohendran, Cho, Iksung, Danad, Ibrahim, Han, Donghee, Heo, Ran, Lee, Ji Hyun, Rivzi, Asim, Stuijfzand, Wijnand J, Gransar, Heidi, Lu, Yao, Sung, Ji Min, Park, Hyung-Bok, Berman, Daniel S, Budoff, Matthew J, Samady, Habib, Shaw, Leslee J, Stone, Peter H, Virmani, Renu, Narula, Jagat, and Min, James K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Heart Disease, Atherosclerosis, Cardiovascular, Heart Disease - Coronary Heart Disease, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Acute Coronary Syndrome, Aged, Case-Control Studies, Cohort Studies, Coronary Artery Disease, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, acute coronary syndrome, atherosclerosis, clinical outcome, coronary artery disease, coronary computed tomography angiography, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThe association of atherosclerotic features with first acute coronary syndromes (ACS) has not accounted for plaque burden.ObjectivesThe purpose of this study was to identify atherosclerotic features associated with precursors of ACS.MethodsWe performed a nested case-control study within a cohort of 25,251 patients undergoing coronary computed tomographic angiography (CTA) with follow-up over 3.4 ± 2.1 years. Patients with ACS and nonevent patients with no prior coronary artery disease (CAD) were propensity matched 1:1 for risk factors and coronary CTA-evaluated obstructive (≥50%) CAD. Separate core laboratories performed blinded adjudication of ACS and culprit lesions and quantification of baseline coronary CTA for percent diameter stenosis (%DS), percent cross-sectional plaque burden (PB), plaque volumes (PVs) by composition (calcified, fibrous, fibrofatty, and necrotic core), and presence of high-risk plaques (HRPs).ResultsWe identified 234 ACS and control pairs (age 62 years, 63% male). More than 65% of patients with ACS had nonobstructive CAD at baseline, and 52% had HRP. The %DS, cross-sectional PB, fibrofatty and necrotic core volume, and HRP increased the adjusted hazard ratio (HR) of ACS (1.010 per %DS, 95% confidence interval [CI]: 1.005 to 1.015; 1.008 per percent cross-sectional PB, 95% CI: 1.003 to 1.013; 1.002 per mm3 fibrofatty plaque, 95% CI: 1.000 to 1.003; 1.593 per mm3 necrotic core, 95% CI: 1.219 to 2.082; all p < 0.05). Of the 129 culprit lesion precursors identified by coronary CTA, three-fourths exhibited

Published
2018

18. Influence of symptom typicality for predicting MACE in patients without obstructive coronary artery disease: From the CONFIRM Registry (Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry).

Author

Lee, Ji Hyun, Han, Donghee, Hartaigh, Bríain Ó, Gransar, Heidi, Lu, Yao, Rizvi, Asim, Park, Mahn Won, Roudsari, Hadi Mirhedayati, Stuijfzand, Wijnand J, Berman, Daniel S, Callister, Tracy Q, DeLago, Augustin, Hadamitzky, Martin, Hausleiter, Joerg, Al-Mallah, Mouaz H, Budoff, Matthew J, Kaufmann, Philipp A, Raff, Gilbert, Chinnaiyan, Kavitha, Cademartiri, Filippo, Maffei, Erica, Villines, Todd C, Kim, Yong-Jin, Leipsic, Jonathon, Feuchtner, Gudrun, Pontone, Gianluca, Andreini, Daniele, Marques, Hugo, Rubinshtein, Ronen, Achenbach, Stephan, Shaw, Leslee J, Chang, Hyuk-Jae, Bax, Jeroen, Chow, Benjamin, Cury, Ricardo C, Gomez, Millie, Jones, Erica C, Lin, Fay Y, Min, James K, and Peña, Jessica M

Subjects
Humans, Angina Pectoris, Angina, Unstable, Coronary Stenosis, Myocardial Infarction, Coronary Angiography, Prognosis, Severity of Illness Index, Registries, Proportional Hazards Models, Risk Factors, Prospective Studies, Predictive Value of Tests, Adult, Aged, Middle Aged, North America, Asia, Europe, Female, Male, Coronary Artery Disease, Kaplan-Meier Estimate, Asymptomatic Diseases, Multidetector Computed Tomography, Computed Tomography Angiography, Coronary Computed Tomographic Angiography, Major Adverse Cardiac Events, Symptom Typicality, Cardiovascular System & Hematology, Cardiorespiratory Medicine and Haematology
Abstract

Our objective was to assess the prognostic value of symptom typicality in patients without obstructive coronary artery disease (CAD), determined by coronary computed tomographic angiography (CCTA). We identified 4215 patients without prior history of CAD and without obstructive CAD (

Published
2018

19. Maximization of the usage of coronary CTA derived plaque information using a machine learning based algorithm to improve risk stratification; insights from the CONFIRM registry

Author

van Rosendael, Alexander R, Maliakal, Gabriel, Kolli, Kranthi K, Beecy, Ashley, Al'Aref, Subhi J, Dwivedi, Aeshita, Singh, Gurpreet, Panday, Mohit, Kumar, Amit, Ma, Xiaoyue, Achenbach, Stephan, Al-Mallah, Mouaz H, Andreini, Daniele, Bax, Jeroen J, Berman, Daniel S, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, DeLago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Joerg, Kaufmann, Philipp A, Kim, Yong-Jin, Leipsic, Jonathon A, Maffei, Erica, Marques, Hugo, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Shaw, Leslee J, Villines, Todd C, Gransar, Heidi, Lu, Yao, Jones, Erica C, Peña, Jessica M, Lin, Fay Y, and Min, James K

Subjects
Information and Computing Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Patient Safety, Atherosclerosis, Heart Disease - Coronary Heart Disease, Basic Behavioral and Social Science, Cardiovascular, Clinical Research, Heart Disease, Biomedical Imaging, Behavioral and Social Science, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Aged, Algorithms, Area Under Curve, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Coronary Stenosis, Coronary Vessels, Female, Humans, Machine Learning, Male, Middle Aged, Multidetector Computed Tomography, Myocardial Infarction, Plaque, Atherosclerotic, Predictive Value of Tests, Prognosis, ROC Curve, Radiographic Image Interpretation, Computer-Assisted, Registries, Reproducibility of Results, Risk Assessment, Risk Factors, Severity of Illness Index, Time Factors, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Applied computing
Abstract

IntroductionMachine learning (ML) is a field in computer science that demonstrated to effectively integrate clinical and imaging data for the creation of prognostic scores. The current study investigated whether a ML score, incorporating only the 16 segment coronary tree information derived from coronary computed tomography angiography (CCTA), provides enhanced risk stratification compared with current CCTA based risk scores.MethodsFrom the multi-center CONFIRM registry, patients were included with complete CCTA risk score information and ≥3 year follow-up for myocardial infarction and death (primary endpoint). Patients with prior coronary artery disease were excluded. Conventional CCTA risk scores (conventional CCTA approach, segment involvement score, duke prognostic index, segment stenosis score, and the Leaman risk score) and a score created using ML were compared for the area under the receiver operating characteristic curve (AUC). Only 16 segment based coronary stenosis (0%, 1-24%, 25-49%, 50-69%, 70-99% and 100%) and composition (calcified, mixed and non-calcified plaque) were provided to the ML model. A boosted ensemble algorithm (extreme gradient boosting; XGBoost) was used and the entire data was randomly split into a training set (80%) and testing set (20%). First, tuned hyperparameters were used to generate a trained model from the training data set (80% of data). Second, the performance of this trained model was independently tested on the unseen test set (20% of data).ResultsIn total, 8844 patients (mean age 58.0 ± 11.5 years, 57.7% male) were included. During a mean follow-up time of 4.6 ± 1.5 years, 609 events occurred (6.9%). No CAD was observed in 48.7% (3.5% event), non-obstructive CAD in 31.8% (6.8% event), and obstructive CAD in 19.5% (15.6% event). Discrimination of events as expressed by AUC was significantly better for the ML based approach (0.771) vs the other scores (ranging from 0.685 to 0.701), P

Published
2018

20. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Author

Giri, Veda N, Knudsen, Karen E, Kelly, William K, Abida, Wassim, Andriole, Gerald L, Bangma, Chris H, Bekelman, Justin E, Benson, Mitchell C, Blanco, Amie, Burnett, Arthur, Catalona, William J, Cooney, Kathleen A, Cooperberg, Matthew, Crawford, David E, Den, Robert B, Dicker, Adam P, Eggener, Scott, Fleshner, Neil, Freedman, Matthew L, Hamdy, Freddie C, Hoffman-Censits, Jean, Hurwitz, Mark D, Hyatt, Colette, Isaacs, William B, Kane, Christopher J, Kantoff, Philip, Karnes, R Jeffrey, Karsh, Lawrence I, Klein, Eric A, Lin, Daniel W, Loughlin, Kevin R, Lu-Yao, Grace, Malkowicz, S Bruce, Mann, Mark J, Mark, James R, McCue, Peter A, Miner, Martin M, Morgan, Todd, Moul, Judd W, Myers, Ronald E, Nielsen, Sarah M, Obeid, Elias, Pavlovich, Christian P, Peiper, Stephen C, Penson, David F, Petrylak, Daniel, Pettaway, Curtis A, Pilarski, Robert, Pinto, Peter A, Poage, Wendy, Raj, Ganesh V, Rebbeck, Timothy R, Robson, Mark E, Rosenberg, Matt T, Sandler, Howard, Sartor, Oliver, Schaeffer, Edward, Schwartz, Gordon F, Shahin, Mark S, Shore, Neal D, Shuch, Brian, Soule, Howard R, Tomlins, Scott A, Trabulsi, Edouard J, Uzzo, Robert, Vander Griend, Donald J, Walsh, Patrick C, Weil, Carol J, Wender, Richard, and Gomella, Leonard G

Subjects
Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Prognosis, Risk Factors, Predictive Value of Tests, Pedigree, Age Factors, Heredity, Phenotype, Adult, Aged, Middle Aged, Male, Genetic Testing, Biomarkers, Tumor, Clinical Decision-Making, Genetics, Aging, Cancer, Prevention, Prostate Cancer, Urologic Diseases, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Published
2018

21. Usefulness of baseline statin therapy in non-obstructive coronary artery disease by coronary computed tomographic angiography: From the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) study

Author

Cho, Yun-Kyeong, Nam, Chang-Wook, Koo, Bon-Kwon, Schulman-Marcus, Joshua, Hartaigh, Bríain Ó, Gransar, Heidi, Lu, Yao, Achenbach, Stephan, Al-Mallah, Mouaz, Andreini, Daniele, Bax, Jeroen J, Budoff, Matthew J, Cademartiri, Filippo, Callister, Tracy Q, Chang, Hyuk-Jae, Chinnaiyan, Kavitha, Chow, Benjamin JW, Cury, Ricardo C, Delago, Augustin, Feuchtner, Gudrun, Hadamitzky, Martin, Hausleiter, Jörg, Kaufmann, Philipp A, Kim, Yong-Jin, Leipsic, Jonathon, Maffei, Erica, Marques, Hugo, Pontone, Gianluca, Raff, Gilbert L, Rubinshtein, Ronen, Shaw, Leslee J, Villines, Todd C, Berman, Daniel S, Jones, Erica C, Peña, Jessica M, Lin, Fay Y, and Min, James K

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Heart Disease - Coronary Heart Disease, Biomedical Imaging, Atherosclerosis, Aging, Cardiovascular, Prevention, Patient Safety, Heart Disease, Clinical Research, Aetiology, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Computed Tomography Angiography, Coronary Artery Disease, Coronary Vessels, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Registries, Treatment Outcome, General Science & Technology
Abstract

BackgroundThe extent to which the presence and extent of subclinical atherosclerosis by coronary computed tomography angiography influences a potential mortality benefit of statin is unknown. We evaluated the relationship between statin therapy, mortality, and subclinical atherosclerosis.MethodsIn the CONFIRM study, patients with normal or non-obstructive plaque (

Published
2018

22. PRINCESS: Privacy-protecting Rare disease International Network Collaboration via Encryption through Software guard extensionS

Author

Chen, Feng, Wang, Shuang, Jiang, Xiaoqian, Ding, Sijie, Lu, Yao, Kim, Jihoon, Sahinalp, S Cenk, Shimizu, Chisato, Burns, Jane C, Wright, Victoria J, Png, Eileen, Hibberd, Martin L, Lloyd, David D, Yang, Hai, Telenti, Amalio, Bloss, Cinnamon S, Fox, Dov, Lauter, Kristin, and Ohno-Machado, Lucila

Subjects
Computer Security, Genetic Association Studies, Genomics, Humans, Mucocutaneous Lymph Node Syndrome, Privacy, Rare Diseases, Software, Mathematical Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract

MotivationWe introduce PRINCESS, a privacy-preserving international collaboration framework for analyzing rare disease genetic data that are distributed across different continents. PRINCESS leverages Software Guard Extensions (SGX) and hardware for trustworthy computation. Unlike a traditional international collaboration model, where individual-level patient DNA are physically centralized at a single site, PRINCESS performs a secure and distributed computation over encrypted data, fulfilling institutional policies and regulations for protected health information.ResultsTo demonstrate PRINCESS' performance and feasibility, we conducted a family-based allelic association study for Kawasaki Disease, with data hosted in three different continents. The experimental results show that PRINCESS provides secure and accurate analyses much faster than alternative solutions, such as homomorphic encryption and garbled circuits (over 40 000× faster).Availability and implementationhttps://github.com/achenfengb/PRINCESS_opensource.Contactshw070@ucsd.edu.Supplementary informationSupplementary data are available at Bioinformatics online.

Published
2017

23. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome.

Author

Kashima, Risa, Roy, Sougata, Ascano, Manuel, Martinez-Cerdeno, Veronica, Ariza-Torres, Jeanelle, Kim, Sunghwan, Louie, Justin, Lu, Yao, Leyton, Patricio, Bloch, Kenneth D, Kornberg, Thomas B, Hagerman, Paul J, Hagerman, Randi, Lagna, Giorgio, and Hata, Akiko

Subjects
Brain, Prefrontal Cortex, Neurons, Neurites, Animals, Mice, Knockout, Humans, Mice, Drosophila melanogaster, Fragile X Syndrome, RNA, Small Interfering, Crosses, Genetic, Autistic Disorder, Signal Transduction, Gene Expression Regulation, Phosphorylation, Heterozygote, Plasmids, Cofilin 1, Bone Morphogenetic Protein Receptors, Type II, Lim Kinases, HEK293 Cells, Protein Domains, Intellectual and Developmental Disabilities (IDD), Autism, Pediatric, Rare Diseases, Brain Disorders, Neurosciences, Mental Health, 2.1 Biological and endogenous factors, Neurological, Knockout, RNA, Small Interfering, Crosses, Genetic, Bone Morphogenetic Protein Receptors, Type II, Biochemistry and Cell Biology
Abstract

Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism.

Published
2016

24. Molecular Signatures of Major Depression

Author

Cai, Na, Chang, Simon, Li, Yihan, Li, Qibin, Hu, Jingchu, Liang, Jieqin, Song, Li, Kretzschmar, Warren, Gan, Xiangchao, Nicod, Jerome, Rivera, Margarita, Deng, Hong, Du, Bo, Li, Keqing, Sang, Wenhu, Gao, Jingfang, Gao, Shugui, Ha, Baowei, Ho, Hung-Yao, Hu, Chunmei, Hu, Jian, Hu, Zhenfei, Huang, Guoping, Jiang, Guoqing, Jiang, Tao, Jin, Wei, Li, Gongying, Li, Kan, Li, Yi, Li, Yingrui, Li, Youhui, Lin, Yu-Ting, Liu, Lanfen, Liu, Tiebang, Liu, Ying, Liu, Yuan, Lu, Yao, Lv, Luxian, Meng, Huaqing, Qian, Puyi, Sang, Hong, Shen, Jianhua, Shi, Jianguo, Sun, Jing, Tao, Ming, Wang, Gang, Wang, Guangbiao, Wang, Jian, Wang, Linmao, Wang, Xueyi, Wang, Xumei, Yang, Huanming, Yang, Lijun, Yin, Ye, Zhang, Jinbei, Zhang, Kerang, Sun, Ning, Zhang, Wei, Zhang, Xiuqing, Zhang, Zhen, Zhong, Hui, Breen, Gerome, Wang, Jun, Marchini, Jonathan, Chen, Yiping, Xu, Qi, Xu, Xun, Mott, Richard, Huang, Guo-Jen, Kendler, Kenneth, and Flint, Jonathan

Subjects
Mental Health, Depression, Neurosciences, Genetics, Human Genome, Behavioral and Social Science, Brain Disorders, Aging, Animals, Biomarkers, Case-Control Studies, Child, Child Abuse, Sexual, DNA, Mitochondrial, Depressive Disorder, Major, Female, Glucocorticoids, Humans, Life Change Events, Male, Mice, Inbred C57BL, Stress, Psychological, Telomere Shortening, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental Biology
Abstract

Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual's somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10(-42), odds ratio 1.33 [95% confidence interval [CI] = 1.29-1.37]) and telomere length (p = 2.84 × 10(-14), odds ratio 0.85 [95% CI = 0.81-0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.

Published
2015

25. Genomic Testing in Localized Prostate Cancer Can Identify Subsets of African Americans With Aggressive Disease

Author

Shivanshu Awasthi, G Daniel Grass, Javier Torres-Roca, Peter A S Johnstone, Julio Pow-Sang, Jasreman Dhillon, Jong Park, Robert J Rounbehler, Elai Davicioni, Alex Hakansson, Yang Liu, Angelina K Fink, Amanda DeRenzis, Jordan H Creed, Michael Poch, Roger Li, Brandon Manley, Daniel Fernandez, Arash Naghavi, Kenneth Gage, Grace Lu-Yao, Evangelia Katsoulakis, Ryan J Burri, Andrew Leone, Cesar E Ercole, Joshua D Palmer, Neha Vapiwala, Curtiland Deville, Timothy R Rebbeck, Adam P Dicker, William Kelly, and Kosj Yamoah

Subjects
Male, Prostatectomy, Black or African American, Cancer Research, Oncology, Humans, Prostatic Neoplasms, Prospective Studies, Genetic Testing, Article
Abstract

Background Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. Methods This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non–African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. Results The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non–African American men). A higher proportion of African American men with National Comprehensive Cancer Network–classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non–African American men. Self-identified African American men were twice more likely than non–African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. Conclusions Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.

Published
2022

26. Development and Validation of a Noninvasive Risk Score Model for Liver Cirrhosis in At-Risk Alcohol Drinkers Without HBV/HCV Infection

Author

Yin Liu, Lan-Wei Guo, Hui-Fang Xu, Rui-Hua Kang, Li-Yang Zheng, Lu-Yao Zhang, Qiong Chen, Xi-Bin Sun, You-Lin Qiao, and Shao-Kai Zhang

Subjects
Liver Cirrhosis, Hepatitis B virus, Cancer Research, Cross-Sectional Studies, Alcohol Drinking, Oncology, Risk Factors, Liver Neoplasms, Humans, Hepatitis C
Abstract

At-risk alcohol consumption is the established most important risk factor for cirrhosis in people without HBV/HCV infection. We aimed to develop and validate a simple and non-invasive tool for triaging cirrhosis risk in at-risk alcohol drinkers without HBV/HCV infection. A large-sample size, cross-sectional study within the framework of a population-based Cancer Screening Program in Urban China (CanSPUC) was conducted. Data on the liver cancer screening in Henan province, China were used. At-risk alcohol drinkers were those who currently drink one or more alcohol units per week for at least six months. A total of 6,581 eligible participants enrolled from October 1, 2013 to December 31, 2016 were included into the derivation dataset, and 2,096 eligible participants enrolled from January 1, 2017 to October 31, 2018 were included into the external validation dataset, respectively. Using the derivation dataset, a 20-point scale risk score model was developed, based on sex, education background, dietary intake of vegetables, dietary intake of roughage, smoking index, length of secondhand smoke exposure, history of fatty liver, history of diabetes, and first-degree family history of liver cancer. The model showed excellent discrimination (AUC = 0.787; 95% CI, 0.7603–0.812) and calibration (Hosmer–Lemeshow test: P = 0.123) in the derivation dataset and an optimal cut-off value of 12 yield sensitivity of 61.3%, specificity of 82.7%. The model also had achieved similar performance in the external validation dataset. In conclusion, this model can be a practical tool to identify and triage population at high risk of cirrhosis in at-risk alcohol drinkers without HBV/HCV infection. Prevention Relevance: The risk model we developed will not only be used as a practical tool to triage high risk groups for liver cirrhosis, but also have implications for public health measures, such as guidelines for the prevention of liver cancer, in at-risk alcohol drinkers without HBV/HCV infection.

Published
2022

27. Retention and impairment of neurocognitive functions in mild cognitive impairment and Alzheimer's disease with a comprehensive neuropsychological test

Author

Lu Yao, Shinsuke Aoyama, Atushi Ouchi, Yasuji Yamamoto, and Ichiro Sora

Subjects
Pharmacology, neurocognitive function, Neuropsychological Tests, Alzheimer's disease, Psychiatry and Mental health, Clinical Psychology, Cognition, mild cognitive impairment, Alzheimer Disease, Schizophrenia, Humans, Cognitive Dysfunction, Pharmacology (medical), cognitive retention, MCCB Japanese version
Abstract

Aim MATRICS Consensus Cognitive Battery was developed by the National Institute of Mental Health to establish acceptance criteria for measuring cognitive changes in schizophrenia and can be used to assess cognitive functions in other psychiatric disorders. We used a Japanese version of MATRICS Consensus Cognitive Battery to explore the changes in multiple cognitive functions in patients with mild cognitive impairment and mild Alzheimer's disease. Methods We administered the Japanese version of MATRICS Consensus Cognitive Battery to 11 patients with mild cognitive impairment (MCI), 11 patients with Alzheimer's disease, and 27 healthy controls. All Japanese versions of MATRICS Consensus Cognitive Battery domain scores were converted to t-scores using sample means and standard deviations and were compared for significant performance differences among healthy control, MCI, and mild Alzheimer's disease groups. Results Compared with healthy controls, patients with MCI and mild Alzheimer's disease demonstrated the same degree of impairment to processing speed, verbal learning, and visual learning. Reasoning and problem-solving showed significant impairments only in mild Alzheimer's disease. Verbal and visual abilities in working memory showed different performances in the MCI and mild Alzheimer's disease groups, with the Alzheimer's disease group demonstrating significantly more deficits in these domains. No significant difference was found among the groups in attention/vigilance and social cognition. Conclusions The Japanese version of MATRICS Consensus Cognitive Battery can be used to elucidate the characteristics of cognitive dysfunction of normal aging, MCI, and mild dementia in clinical practice.

Published
2022

29. Special issue 'The advance of solid tumor research in China': Participants with a family history of cancer have a higher participation rate in low‐dose computed tomography for lung cancer screening

Author

Lan‐Wei Guo, Qing‐Cheng Meng, Li‐Yang Zheng, Qiong Chen, Yin Liu, Hui‐Fang Xu, Rui‐Hua Kang, Lu‐Yao Zhang, Shu‐Zheng Liu, Xi‐Bin Sun, and Shao‐Kai Zhang

Subjects
China, Cancer Research, Lung Neoplasms, Oncology, Humans, Mass Screening, Tomography, X-Ray Computed, Early Detection of Cancer
Abstract

We aimed to determine participation in low-dose computed tomography (LDCT) of individuals with a family history of common cancers in a population-based screening program to provide timely evidence in high-risk populations in China. The analysis was conducted using data from the Cancer Screening Program in Urban China (CanSPUC), which recruited 282 377 participants aged 40 to 74 years from eight cities in the Henan province. Using the CanSPUC risk score system, 55 428 participants were evaluated to have high risk for lung cancer and were recommended for LDCT. We calculated the overall and group-specific participation rates using family history of common cancers and compared differences in participation rates between different groups. Odds ratios (ORs) and 95% confidence intervals were derived by multivariable logistic regression. Of the 55 428 participants, 22 260 underwent LDCT (participation rate, 40.16%). Family history of lung, esophageal, stomach, liver and colorectal cancer was associated with increased participation in LDCT screening. The odds of participants with a family history of one, two, three and four or more cancer cases undergoing LDCT screening were 1.9, 2.7, 2.8 and 3.5 times, respectively, than those without a family history of cancer. Compared to those without a history of cancer, participation in LDCT gradually increased as the number of cancer cases in the family increased (P .001). Our findings suggest that there is room for improvement in lung cancer screening given the relatively low participation rate. Lung cancer screening in populations with a family history of cancer may improve efficiency and cost-effectiveness; however, this requires further verification.

Published
2022

30. International trends in cancer incidence in middle-aged and older adults in 44 countries

Author

Sophie Pilleron, Naser Alqurini, Jacques Ferlay, Kristen R. Haase, Michelle Hannan, Maryska Janssen-Heijnen, Kumud Kantilal, Kota Katanoda, Cindy Kenis, Grace Lu-Yao, Tomohiro Matsuda, Erna Navarrete, Nikita Nikita, Martine Puts, Fay J. Strohschein, Eva J.A. Morris, Epidemiologie, and RS: GROW - R1 - Prevention

Subjects
RISK, Male, Skin Neoplasms, Epidemiology, IMPACT, MORTALITY, Incidence, Breast Neoplasms, CHEMOTHERAPY, Population-based cancer registries, Middle Aged, PROSTATE-CANCER, Oncology, Neoplasms, Older adults, Republic of Korea, BREAST-CANCER, Humans, Female, Registries, Trends, Geriatrics and Gerontology, POPULATION, Aged
Abstract

Objective: We examine international incidence trends of lung, colorectal, prostate, and breast cancers, as well as all cancers combined excluding non-melanoma skin cancer (NMSC) in adults aged 50 and older, over a fifteen-year period using data from 113 high quality population-based cancer registries included in the Cancer in Five Continents (CI5) series and NORDCAN. Materials and methods: We calculated annual incidence rates between 1998 and 2012 for ages 50–64, 65–74, and 75+, by sex and both sexes combined. We estimated average annual percentage change (AAPC) in rates using quasi-Poisson regression models. Results: From 1998 to 2012, incidence trends for all cancers (excluding NMSC) have increased in most countries across all age groups, with the greatest increase observed in adults aged 75+ in Ecuador (AAPC = +3%). Colorectal cancer incidence rates increased in the majority of countries, across all age groups. Lung cancer rates among females have increased but decreased for males. Prostate cancer rates have sharply increased in men aged 50–64 with AAPC between 5% and 15% in 24 countries, while decreasing in the 75+ age group in 21 countries, by up to −7% in Bahrain. Female breast cancer rates have increased across all age groups in most countries, especially in the 65–74 age group and in Asia with AAPC increasing to 7% in the Republic of Korea. Conclusions: These findings assist with anticipating changing patterns and needs internationally. Due to the specific needs of older patients, it is urgent that cancer systems adapt to address their growing number.

Published
2022

31. A risk prediction model for selecting high-risk population for computed tomography lung cancer screening in China

Author

Jiangong Zhang, Hui-Fang Xu, Xibin Sun, Lan-Wei Guo, Rui-hua Kang, Zhang-Yan Lyu, Qing-Cheng Meng, Shaokai Zhang, Shu-Zheng Liu, Xiaoqin Cao, Lu-yao Zhang, Liyang Zheng, Yin Liu, and Qiong Chen

Subjects
Male, Pulmonary and Respiratory Medicine, China, Cancer Research, medicine.medical_specialty, education.field_of_study, Lung Neoplasms, medicine.diagnostic_test, business.industry, Population, Computed tomography, Risk Assessment, Oncology, Risk Factors, Humans, Mass Screening, Medicine, Female, Radiology, Tomography, X-Ray Computed, business, education, Early Detection of Cancer, Lung cancer screening
Abstract

Two large randomized controlled trials (RCTs) have demonstrated that low dose computed tomography (LDCT) screening reduces lung cancer mortality. Risk-prediction models have been proved to select individuals for lung cancer screening effectively. With the focus on established risk factors for lung cancer routinely available in general cancer screening settings, we aimed to develop and internally validated a risk prediction model for lung cancer.Using data from the Cancer Screening Program in Urban China (CanSPUC) in Henan province, China between 2013 and 2019, we conducted a prospective cohort study consisting of 282,254 participants including 126,445 males and 155,809 females. Detailed questionnaire, physical assessment and follow-up were completed for all participants. Using Cox proportional risk regression analysis, we developed the Henan Lung Cancer Risk Models based on simplified questionnaire. Model discrimination was evaluated by concordance statistics (C-statistics), and model calibration was evaluated by the bootstrap sampling, respectively.By 2020, a total of 589 lung cancer cases occurred in the follow-up yielding an incident density of 64.91/100,000 person-years (pyrs). Age, gender, smoking, history of tuberculosis and history of emphysema were included into the model. The C-index of the model for 1-year lung cancer risk was 0.766 and 0.741 in the training set and validation set, respectively. In stratified analysis, the model showed better predictive power in males, younger participants, and former or current smoking participants. The model calibrated well across the deciles of predicted risk in both the overall population and all subgroups.We developed and internally validated a simple risk prediction model for lung cancer, which may be useful to identify high-risk individuals for more intensive screening for cancer prevention.

Published
2022

32. The mechanism of Bai He Gu Jin Tang against non-small cell lung cancer revealed by network pharmacology and molecular docking

Author

Rui-fei Xie, Zi-yu Song, Lu-yao Xu-shao, Jin-ge Huang, Ting Zhao, and Zi Yang

Subjects
Male, Molecular Docking Simulation, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Humans, General Medicine, Network Pharmacology, Neoplasm Recurrence, Local, Medicine, Chinese Traditional, Drugs, Chinese Herbal
Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related burden and deaths, thus effective treatment strategies with lower side effects for NSCLC are urgently needed. To systematically analyze the mechanism of Bai He Gu Jin Tang (BHGJT) against NSCLC by network pharmacology and molecular docking.The active compounds of BHGJT were obtained by searching the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and Encyclopaedia of Traditional Chinese Medicine. Search tool for interactions of chemicals was used for acquiring the targets of BHGJT. The component-target network was mapped by Cytoscape. NSCLC-related genes were obtained by searching Genecards, DrugBank and Therapeutic Target Database. The protein-protein interaction network of intersection targets was established based on Search Tool for Recurring Instances of Neighboring Genes (STRING), and further, the therapeutic core targets were selected by topological parameters. The hub targets were transmitted to Database for Annotation, Visualization and Integrated Discovery for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, AutoDock Vina and MglTools were employed for molecular docking validation.Two hundred fifty-six compounds and 237 putative targets of BHGJT-related active compounds as well as 1721potential targets of NSCLC were retrieved. Network analysis showed that 8 active compounds of BHGJT including kaempferol, quercetin, luteolin, isorhamnetin, beta-sitosterol, stigmasterol, mairin and liquiritigenin as well as 15 hub targets such as AKR1B10 and AKR1C2 contribute to the treatment of BHGJT against NSCLC. GO functional enrichment analysis shows that BHGJT could regulate many biological processes, such as apoptotic process. Three modules of the endocrine related pathways including the inflammation, hypoxia related pathways as well as the other cancer related pathways based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis might explain the biological mechanisms of BHGJT in treating BHGJT. The results of molecular docking verified that AKR1B10 and AKR1C2 had the strongest binding activity with the 8 key compounds of NSCLC.Our study reveals the mechanism of BHGJT in treating NSCLC involving multiple components, multiple targets and multiple pathways. The present study laid an initial foundation for the subsequent research and clinical application of BHGJT and its active compounds against NSCLC.

Published
2023

33. Risk of Liver Cirrhosis in HBV/HCV-Infected Individuals with First-Degree Relatives Who Have Liver Cancer: Development and Validation of a Simple Model

Author

You-Lin Qiao, Rui-hua Kang, Xi Bin Sun, Shaokai Zhang, Lanwei Guo, Hui-Fang Xu, Qiong Chen, Liyang Zheng, Yin Liu, and Lu-yao Zhang

Subjects
Liver Cirrhosis, Hepatitis B virus, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Population, Prevalence, Logistic regression, Risk Factors, Internal medicine, Cancer screening, medicine, Humans, First-degree relatives, education, education.field_of_study, Framingham Risk Score, business.industry, Liver Neoplasms, Hepatitis B, medicine.disease, Hepatitis C, Cross-Sectional Studies, Oncology, Liver cancer, business
Abstract

Identification of high-risk population among hepatitis B virus (HBV)/hepatitis C virus (HCV)-infected individuals with first-degree relatives (FDR) who have liver cancer is important to implement precise intervention. A cross-sectional study was conducted under the framework of a population-based Cancer Screening Program in Urban China (CanSPUC), aimed to develop and validate a simple noninvasive model that could assess and stratify cirrhosis risk, in HBV/HCV-infected individuals with FDRs who have liver cancer. People who participated in liver cancer screening in Henan province were enrolled. Using the data set consisting of participants admitted from October 1, 2013, to December 31, 2016, a 24-point scale risk score model was developed through logistic regression, based on educational background, dietary habit, smoking index, cooking oil fume exposure, history of severe trauma, HBV/HCV infection status, history of diabetes, history of hyperlipidemia, and parent history of liver cancer. The model showed excellent discrimination with area under the receiver operator characteristic curve (AUROC) of 0.875 [95% confidence interval (CI), 0.853–0.896] and fair calibration with a Hosmer–Lemeshow test P = 0.106. The prevalence rates in the medium- and high-risk groups were 2.87 (95% CI, 1.94–4.25) and 47.57 (95% CI, 31.59–71.63) times of low-risk group, respectively. After internal validation, bias-corrected AUROC was 0.874 (95% CI, 0.873–0.875). In the external validation data set consisting of participants admitted from January 1, 2017, to October 31, 2018, the model had achieved similar discrimination, calibration, and risk stratification ability. In conclusion, the risk score model we developed can be a practical tool for the screening and prevention of liver cirrhosis among HBV/HCV-infected individuals with FDRs who have liver cancer. Prevention Relevance: We created a simple and noninvasive cirrhosis risk model for individuals infected by HBV/HCV who have FDRs with liver cancer. This model is useful not only for the prognosis of HBV/HCV infection, but also for the prevention of hepatocellular carcinoma.

Published
2021

34. A familial cluster of COVID-19 infection in a northern Chinese region

Author

Lu-yao Sun, Cai-xia Liu, Yi-zhe Sun, Kai-yu Zhang, and Zhi-hui Liu

Subjects
medicine.medical_specialty, China, 2019-nCoV, 2019 novel coronavirus, RT-PCR, reverse transcription-polymerase chain reaction, WBCs, white blood cells, Infectious and parasitic diseases, RC109-216, Disease cluster, medicine.disease_cause, ACE2, angiotensin-converting enzyme 2, WHO, World Health Organization, law.invention, Incubation period, Disease Outbreaks, law, Internal medicine, Epidemiology, Quarantine, Global health, medicine, Humans, Coronavirus, COVID-19, coronavirus disease 2019, ESR, erythrocyte sedimentation rate, SARS-CoV-2, severe acute respiratory coronavirus 2, Coronavirus disease 2019, business.industry, SARS-CoV-2, Family cluster, Public Health, Environmental and Occupational Health, Outbreak, COVID-19, General Medicine, Infectious Diseases, NCP, Novel Coronavirus Pneumonia, CRP, C-reactive protein, CT, Computed tomography, Original Article, Public aspects of medicine, RA1-1270, business, Asymptomatic carrier
Abstract

Objective Currently, coronavirus disease 2019 (COVID-19) has spread worldwide and become a global health concern. Here, we report a familial cluster of six patients infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) in a northern Chinese region and share our local experience with regard the control of COVID-19. Methods The demographic data, clinical features, laboratory examinations, and epidemiological characteristics of enrolled cases were collected and analyzed. Two family members (Cases 1 and 2) had Hubei exposure history and were admitted to the hospital with a confirmed diagnosis of COVID-19; eight familial members who had contact with them during the incubation period underwent quarantine in a hospital. We closely followed up all the family members and analyzed their clinical outcome. Results Case 3 had negative SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) results but was suspected to have COVID-19 because of radiographic abnormalities. Cases 4 and 5 developed symptomatic COVID-19. Case 6 was considered an asymptomatic carrier as his SARS-CoV-2 RT-PCR result was positive. The other four family members with close contacts to COVID-19 patients had no evidence of SARS-CoV-2 infection. Conclusions Our findings suggest that COVID-19 has infectivity during the incubation period and preventive quarantine is effective for controlling an outbreak of COVID-19 infection.

Published
2021

35. Correlation between serum trimethylamine

Author

Chun, Hu, Yumei, Zhang, Xiao, Bi, Lu, Yao, Yueling, Zhou, and Wei, Ding

Subjects
Methylamines, Renal Dialysis, Humans, Oxides, Dietary Proteins, Renal Insufficiency, Chronic, Protein-Energy Malnutrition
Abstract

Chronic kidney disease (CKD) is a serious health problem that is associated with several systemic changes, including protein energy wasting (PEW). However, the exact mechanism of PEW in CKD remains unclear. As one of the important intestinal flora metabolites and uremic toxins, trimethylamine-PEW was diagnosed in a group of CKD patients on MHD according to the criteria of the International Society of Renal Nutrition and Metabolism. Serum TMAO concentration was assessed by high-performance liquid chromatography and mass spectrometry. The association between TMAO concentration and PEW was assessed using linear regression and logistic analysis after adjustment for confounding factors, including basic characteristics, comorbidities, and laboratory findings.The circulating TMAO level was higher in the MHD patients than in control (healthy) individuals (5653.76 ± 2853.51 vs. 254.92 ± 197.88 ng/mL,The circulating TMAO level is significantly correlated with the prevalence of PEW in MHD patients. TMAO might be a potential target in the prevention and treatment of PEW in CKD especially ESRD.

Published
2022

36. [Characteristics of Carbonaceous Species in PM

Author

Lu-Yao, Chen, Yang-Chun, Yu, Xiao-Juan, Huang, Gui-Ming, Dong, and Jun-Ke, Zhang

Subjects
Aerosols, Air Pollutants, Humans, Particulate Matter, Particle Size, Carbon, Environmental Monitoring
Abstract

The Air Pollution Prevention and Control Action Plan and Three-year Plan on Defending the Blue Sky promulgated by the State Council of the People's Republic of China have played an important role in the overall improvement of air quality in China. However, few studies have evaluated the implementation effects of these two policies in Sichuan Basin and the new characteristics of PM

Published
2022

37. Cortisol Stimulates Local Progesterone Withdrawal Through Induction of AKR1C1 in Human Amnion Fibroblasts at Parturition

Author

Jiang-Wen Lu, Wen-Jia Lei, Li-Jun Ling, Lu-Yao Wang, Yi-Kai Lin, Fan Zhang, Meng-Die Li, Fan Pan, Wang-Sheng Wang, and Kang Sun

Subjects
CCAAT-Enhancer-Binding Protein-delta, Hydrocortisone, Aldo-Keto Reductases, Parturition, Fibroblasts, Dinoprostone, Endocrinology, Pregnancy, Cyclooxygenase 2, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Humans, Female, Amnion, Progesterone
Abstract

Fetal membrane activation is seen as being one of the crucial triggering components of human parturition. Increased prostaglandin E2 (PGE2) production, a common mediator of labor onset in virtually all species, is recognized as one of the landmark events of membrane activation. Fetal membranes are also equipped with a high capacity of cortisol regeneration by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), and the cortisol regenerated potently induces PGE2 synthesis, an effect normally suppressed by progesterone during gestation. There is no precipitous decline of progesterone synthesis in human parturition. It is intriguing how this suppression is lifted in parturition. Here, we investigated this issue by using human amnion tissue and primary amnion fibroblasts which synthesize the most PGE2 in the fetal membranes. Results showed that the expression of 11β-HSD1 and aldo-keto reductase family 1 member C1 (AKR1C1), a progesterone-inactivating enzyme, increased in parallel in human amnion tissue with gestational age toward the end of gestation and at parturition. Cortisol induced AKR1C1 expression via the transcription factor CCAAT enhancer binding protein δ (C/EBPδ) in amnion fibroblasts. Inhibition of AKR1C1 not only blocked progesterone catabolism induced by cortisol, but also enhanced the suppression of cortisol-induced cyclooxygenase-2 (COX-2) expression by progesterone in amnion fibroblasts. In conclusion, our results indicate that cortisol regenerated in the fetal membranes triggers local progesterone withdrawal through enhancement of AKR1C1-mediated progesterone catabolism in amnion fibroblasts, so that the suppression of progesterone on the induction of COX-2 expression and PGE2 synthesis by cortisol can be lifted for parturition.

Published
2022

38. The potential role of abnormal angiotensin-converting enzyme 2 expression correlated with immune infiltration after SARS-CoV-2 infection in the prognosis of breast cancer

Author

Yufeng Jiang, Ling Chen, Tan Chen, Xiaofei Mei, Jia-Lu Yao, Yafeng Zhou, and Jinsheng Shen

Subjects
Aging, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), T cell, ACE2, Breast Neoplasms, Kaplan-Meier Estimate, Mice, Breast cancer, Lymphocytes, Tumor-Infiltrating, Immune infiltration, Chlorocebus aethiops, Biomarkers, Tumor, Medicine, Animals, Humans, skin and connective tissue diseases, Vero Cells, business.industry, SARS-CoV-2, immune infiltration, COVID-19, Cell Biology, medicine.disease, Prognosis, CD8A, medicine.anatomical_structure, Angiotensin-converting enzyme 2, Vero cell, Cancer research, Female, Angiotensin-Converting Enzyme 2, business, CD8, hormones, hormone substitutes, and hormone antagonists, Research Paper
Abstract

The potential role of abnormal ACE2 expression after SARS-CoV-2 infection in the prognosis of breast cancer is still ambiguous. In this study, we analyzed ACE2 changes in breast cancer and studied the correlation between ACE2 and the prognosis and further analyzed the relationship between immune infiltration and the prognosis of different breast cancer subtypes. Finally, we inferred the prognosis of breast cancer patients after SARS-CoV-2 infection. We found that ACE2 expression decreased significantly in breast cancer, except for basal-like subtype. Decreased ACE2 expression level was correlated with abnormal immune infiltration and poorer prognosis of luminal B breast cancer (RFS: HR 0.76, 95%CI=0.63-0.92, p=0.005; DMFS: HR 0.70, 95%CI=0.49-1.00, p=0.046). The expression of ACE2 was strongly positively correlated with the immune infiltration level of CD8+ T cell (r=0.184, p

Published
2021

39. Delayed cholecystectomy following endoscopic retrograde cholangio-pancreatography is not associated with worse surgical outcomes

Author

Muhammad Abdalkoddus, Joshua Franklyn, Somaiah Aroori, Rashid Ibrahim, Nur Zainudin, and Lu Yao

Subjects
medicine.medical_specialty, medicine.medical_treatment, Article, ERCP, Internal medicine, medicine, Humans, Bile leak, Retrospective Studies, Cholangiopancreatography, Endoscopic Retrograde, Common bile duct exploration, business.industry, Significant difference, Hepatology, University hospital, Surgery, Choledocholithiasis, Treatment Outcome, Cholecystectomy, Laparoscopic, Cholecystectomy, business, Abdominal surgery, Endoscopic retrograde cholangio-pancreatography, Delayed cholecystectomy
Abstract

Background There is no universal consensus on the optimal timing of cholecystectomy following endoscopic retrograde cholangio-pancreatography (ERCP). This study aims to evaluate the effect of time delay and post-ERCP complications on cholecystectomy outcomes. Materials and methods All patients who underwent pre-op ERCP for concurrent cholelithiasis and choledocholithiasis between January 2009 and August 2019 at University Hospitals Plymouth, UK, were included. Patients who underwent single-stage cholecystectomy and common bile duct exploration were excluded from the study. Based on the delay to cholecystectomy, the patients were divided into early (within 2 weeks), intermediate (2–6 weeks) and late (> 6 weeks) groups. The operative outcomes between the three groups were compared. Results We included 444 patients in the study, with 62 (14%), 90 (20%) and 292 (66%) patients in the early, intermediate and late groups, respectively. The median duration from ERCP to cholecystectomy was 75 days. There was no statistically significant difference in the conversion-to-open rate, bile leak rate or retained stones between the three groups. The median post-operative hospital stay (PHS) was 2, 2 and 1 day (P = 0.005) in the early, intermediate and late groups, respectively. The readmission rate was significantly more in the delayed group (3.2%, 11.1% and 13.7%; P = 0.05). Patients who suffered post-ERCP complications had a significantly longer PHS (4 vs 1 day, P = 0.001) and had higher conversion-to-open rate (16 vs 4.5%, P = 0.04). Conclusion Delayed cholecystectomy following ERCP is not associated with worse peri-operative outcomes and can facilitate more day-case surgery. However, early cholecystectomy can significantly reduce readmissions with gallstone-related symptoms and its associated hospital stay. Post-ERCP complications lead to a difficult cholecystectomy.

Published
2021

40. FCGR2C: An emerging immune gene for predicting sepsis outcome

Author

Si Liu, Yao Lu Zhang, Lu Yao Zhang, Guang Ju Zhao, and Zhong Qiu Lu

Subjects
Immunosuppression Therapy, Neutrophils, Sepsis, Immunology, Immunology and Allergy, Humans, Biomarkers, APACHE
Abstract

BackgroundSepsis is a life-threatening disease associated with immunosuppression. Immunosuppression could ultimately increase sepsis mortality. This study aimed to identify the prognostic biomarkers related to immunity in sepsis.MethodsPublic datasets of sepsis downloaded from the Gene Expression Omnibus (GEO) database were divided into the discovery cohort and the first validation cohort. We used R software to screen differentially expressed genes (DEGs) and analyzed DEGs’ functional enrichment in the discovery dataset. Immune-related genes (IRGs) were filtered from the GeneCards website. A Lasso regression model was used to screen candidate prognostic genes from the intersection of DEGs and IRGs. Then, the candidate prognostic genes with significant differences were identified as prognostic genes in the first validation cohort. We further validated the expression of the prognostic genes in the second validation cohort of 81 septic patients recruited from our hospital. In addition, we used four immune infiltration methods (MCP-counter, ssGSEA, ImmuCellAI, and CIBERSORT) to analyze immune cell composition in sepsis. We also explored the correlation between the prognostic biomarker and immune cells.ResultsFirst, 140 genes were identified as prognostic-related immune genes from the intersection of DEGs and IRGs. We screened 18 candidate prognostic genes in the discovery cohort with the lasso regression model. Second, in the first validation cohort, we identified 4 genes (CFHR2, FCGR2C, GFI1, and TICAM1) as prognostic immune genes. Subsequently, we found that FCGR2C was the only gene differentially expressed between survivors and non-survivors in 81 septic patients. In the discovery and first validation cohorts, the AUC values of FCGR2C were 0.73 and 0.67, respectively. FCGR2C (AUC=0.84) had more value than SOFA (AUC=0.80) and APACHE II (AUC=0.69) in evaluating the prognosis of septic patients in our recruitment cohort. Moreover, FCGR2C may be closely related to many immune cells and functions, such as B cells, NK cells, neutrophils, cytolytic activity, and inflammatory promotion. Finally, enrichment analysis showed that FCGR2C was enriched in the phagosome signaling pathway.ConclusionFCGR2C could be an immune biomarker associated with prognosis, which may be a new direction of immunotherapy to reduce sepsis mortality.

Published
2022

41. Electrochemical label-free immunoassay of HE4 using 3D PtNi nanocubes assemblies as biosensing interfaces

Author

Di-Nan Chen, Lu-Yao Jiang, Jing-Xian Zhang, Chang Tang, Ai-Jun Wang, and Jiu-Ju Feng

Subjects
Immunoassay, Ovarian Neoplasms, Biomarkers, Tumor, Humans, Female, Biosensing Techniques, Early Detection of Cancer, Analytical Chemistry
Abstract

Human epididymis protein 4 (HE4) is a vital biomarker for early diagnosis of epithelial ovarian cancer (EOC). Herein, a new label-free biosensor was developed using K

Published
2022

42. Immunomodulation by foods and microbes: Unravelling the molecular tango

Author

Brian Forde, Lu Yao, Rupin Shaha, Sally Murphy, Nonhlanhla Lunjani, and Liam O'Mahony

Subjects
Immunomodulation, Immunology, Immunity, Immunology and Allergy, Humans, Dysbiosis, Food Hypersensitivity, Asthma
Abstract

Metabolic health and immune function are intimately connected via diet and the microbiota. Nearly 90% of all immune cells in the body are associated with the gastrointestinal tract and these immune cells are continuously exposed to a wide range of microbes and microbial-derived compounds, with important systemic ramifications. Microbial dysbiosis has consistently been observed in patients with atopic dermatitis, food allergy and asthma and the molecular mechanisms linking changes in microbial populations with disease risk and disease endotypes are being intensively investigated. The discovery of novel bacterial metabolites that impact immune function is at the forefront of host-microbe research. Co-evolution of microbial communities within their hosts has resulted in intertwined metabolic pathways that affect physiological and pathological processes. However, recent dietary and lifestyle changes are thought to negatively influence interactions between microbes and their host. This review provides an overview of some of the critical metabolite-receptor interactions that have been recently described, which may underpin the immunomodulatory effects of the microbiota, and are of relevance for allergy, asthma and infectious diseases.

Published
2022

43. A sandwich-type electrochemical immunosensor for CYFRA 21–1 based on probe-confined in PtPd/polydopamine/hollow carbon spheres coupled with dendritic Au@Rh nanocrystals

Author

Yi-Ge Feng, Jia-Wen He, Di-Nan Chen, Lu-Yao Jiang, Ai-Jun Wang, Ning Bao, and Jiu-Ju Feng

Subjects
Immunoassay, Keratin-19, Indoles, Lung Neoplasms, Antigens, Neoplasm, Polymers, Carcinoma, Non-Small-Cell Lung, Humans, Nanoparticles, Biosensing Techniques, Antibodies, Carbon, Analytical Chemistry
Abstract

A signal-on sandwich-like electrochemical immunosensor was built for determination of cytokeratin 19 fragments 21-1 (CYFRA 21-1) in non-small cell lung cancer (NSCLC) by confining electroactive dye (e.g., methylene blue, MB) as a probe for amplifying signals. Specifically, core-shell gold@rhodium dendritic nanocrystals (Au@Rh DNCs) behaved as a substrate for primary antibody and accelerate interfacial electron transfer. Besides, hollow carbon spheres (HCSs) were subsequently modified with polydopamine (PDA) and PtPd nanoparticles for sequential integration of the secondary antibody and confinement of MB as a label, termed as MB/PtPd/PDA/HCSs for clarity. The built sensors showed a broad linear range (100 fg mL

Published
2022

44. Ultrasensitive sandwich-typed electrochemical immunoassay for detection of squamous cell carcinoma antigen based on highly branched PtCo nanocrystals and dendritic mesoporous SiO

Author

Jing-Xian, Zhang, Chun-Lin, Lv, Chang, Tang, Lu-Yao, Jiang, Ai-Jun, Wang, and Jiu-Ju, Feng

Subjects
Immunoassay, Antigens, Neoplasm, Limit of Detection, Biomarkers, Tumor, Humans, Metal Nanoparticles, Reproducibility of Results, Female, Biosensing Techniques, Electrochemical Techniques, Gold, Silicon Dioxide, Serpins
Abstract

Squamous cell carcinoma antigen (SCCA) is one of the common squamous cell carcinomas (SCC) in women, which usually works as a tumor biomarker for cervical cancer in diagnostic applications. Herein, bimetallic PtCo highly branched nanocrystals (PtCo BNCs) acted as electrode substrates to construct sandwich-typed electrochemical immunosensor for ultrasensitive detection of SCCA, by using dendritic mesoporous SiO

Published
2022

45. Clinical characteristics and risk factors associated with ICU-acquired infections in sepsis: A retrospective cohort study

Author

Yajun He, Jiqian Xu, Xiaopu Shang, Xiangzhi Fang, Chenggang Gao, Deyi Sun, Lu Yao, Ting Zhou, Shangwen Pan, Xiaojing Zou, Huaqing Shu, Xiaobo Yang, and You Shang

Subjects
Microbiology (medical), Intensive Care Units, Infectious Diseases, Organ Dysfunction Scores, Risk Factors, Sepsis, Immunology, Humans, Microbiology, Retrospective Studies
Abstract

Intensive care unit (ICU)-acquired infection is a common cause of poor prognosis of sepsis in the ICU. However, sepsis-associated ICU-acquired infections have not been fully characterized. The study aims to assess the risk factors and develop a model that predicts the risk of ICU-acquired infections in patients with sepsis.MethodsWe retrieved data from the Medical Information Mart for Intensive Care (MIMIC) IV database. Patients were randomly divided into training and validation cohorts at a 7:3 ratio. A multivariable logistic regression model was used to identify independent risk factors that could predict ICU-acquired infection. We also assessed its discrimination and calibration abilities and compared them with classical score systems.ResultsOf 16,808 included septic patients, 2,871 (17.1%) developed ICU-acquired infection. These patients with ICU-acquired infection had a 17.7% ICU mortality and 31.8% in-hospital mortality and showed a continued rise in mortality from 28 to 100 days after ICU admission. The classical Systemic Inflammatory Response Syndrome Score (SIRS), Sequential Organ Failure Assessment (SOFA), Oxford Acute Severity of Illness Score (OASIS), Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction Score (LODS), Charlson Comorbidity Index (CCI), and Acute Physiology Score III (APS III) scores were associated with ICU-acquired infection, and cerebrovascular insufficiency, Gram-negative bacteria, surgical ICU, tracheostomy, central venous catheter, urinary catheter, mechanical ventilation, red blood cell (RBC) transfusion, LODS score and anticoagulant therapy were independent predictors of developing ICU-acquired infection in septic patients. The nomogram on the basis of these independent predictors showed good calibration and discrimination in both the derivation (AUROC = 0.737; 95% CI, 0.725–0.749) and validation (AUROC = 0.751; 95% CI, 0.734–0.769) populations and was superior to that of SIRS, SOFA, OASIS, SAPS II, LODS, CCI, and APS III models.ConclusionsICU-acquired infections increase the likelihood of septic mortality. The individualized prognostic model on the basis of the nomogram could accurately predict ICU-acquired infection and optimize management or tailored therapy.

Published
2022

46. Prevalence of BRCA1 and BRCA2 pathogenic variants in 8627 unselected patients with breast cancer: stratification of age at diagnosis, family history and molecular subtype

Author

Fan Zang, Xinyun Ding, Jiuan Chen, Li Hu, Jie Sun, Juan Zhang, Ye Xu, Lu Yao, and Yuntao Xie

Subjects
BRCA2 Protein, Cancer Research, Oncology, BRCA1 Protein, Genes, BRCA2, Prevalence, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Germ-Line Mutation
Abstract

Comprehensively analyzing the prevalence of BRCA1/2 germline pathogenic variants (PVs) in a large cohort of unselected Chinese patients with breast cancer has great clinical importance.Germline pathogenic variants in full-length BRCA1/2 genes were determined through next-generation sequencing and/or Sanger sequencing assays in 8627 unselected Chinese patients with breast cancer who were treated at the Breast Center of Peking University Cancer Hospital. The prevalence of BRCA1/2 PVs was further stratified by age at diagnosis, family history of cancer and molecular subtype.We found that the overall prevalence of BRCA1/2 PVs was 6.0% in the entire cohort, 2.4% in BRCA1 and 3.7% in BRCA2. The prevalence of BRCA1/2 PVs in patients with early-onset breast cancer (age at diagnosis ≤ 40 years) was significantly higher than that in patients over the age of 40 (9.7% vs. 5.1%). The prevalence rates of BRCA1/2 PVs in patients with a family history of breast, ovarian, pancreatic, and prostate cancer were 19.5%, 39.0%, 11.1%, and 12.8%, respectively. Moreover, the number of relatives affected by breast cancer was associated with a higher prevalence of BRCA1/2 PVs. Molecular subtypes were associated with the prevalence of BRCA1/2 PVs. Patients with the triple-negative phenotype had the highest prevalence of BRCA1/2 PVs (13.3%) among the three molecular groups, followed by the HR + and HER2- group (5.9%), and the lowest was in the HER2 + group (2.5%).Our study provides the most comprehensive information to date on the prevalence of BRCA1/2 PVs in unselected Chinese patients with breast cancer.

Published
2022

47. In vivo activation of pH-responsive oxidase-like graphitic nanozymes for selective killing of Helicobacter pylori

Author

Liang Zhang, Hui Deng, Weihong Tan, Lufeng Zhang, Ye Qiu, Zhuo Chen, Michael J. Donovan, Huan Li, Lu-Yao Guan, and Wentao Tang

Subjects
Helicobacter pylori infection, Science, General Physics and Astronomy, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, Article, Microbiology, Helicobacter Infections, Gastric Acid, Mice, In vivo, Animals, Humans, chemistry.chemical_classification, Reactive oxygen species, Oxidase test, Multidisciplinary, biology, Helicobacter pylori, Antimicrobials, General Chemistry, Hydrogen-Ion Concentration, 021001 nanoscience & nanotechnology, biology.organism_classification, 0104 chemical sciences, Gastric ph, Anti-Bacterial Agents, Nanomedicine, chemistry, Gastric Mucosa, Gastric acid, Graphite, 0210 nano-technology, Oxidoreductases, Reactive Oxygen Species, Symbiotic bacteria
Abstract

Helicobacter pylori infection is a major etiological factor in gastric diseases. However, clinical antibiotic therapy for H. pylori is limited by continuously decreased therapeutic efficacy and side effects to symbiotic bacteria. Herein, we develop an in vivo activatable pH-responsive graphitic nanozyme, PtCo@Graphene (PtCo@G), for selective treatment of H. pylori. Such nanozymes can resist gastric acid corrosion, exhibit oxidase-like activity to stably generate reactive oxygen species only in acidic gastric milieu and demonstrate superior selective bactericidal property. C18-PEGn-Benzeneboronic acid molecules are modified on PtCo@G, improving its targeting capability. Under acidic gastric pH, graphitic nanozymes show notable bactericidal activity toward H. pylori, while no bacterial killing is observed under intestinal conditions. In mouse model, high antibacterial capability toward H. pylori and negligible side effects toward normal tissues and symbiotic bacteria are achieved. Graphitic nanozyme displays the desired enzyme-like activities at corresponding physiological sites and may address critical issues in clinical treatment of H. pylori infections., Helicobacter pylori is a major cause of gastric diseases, but the standard therapy is limited by continuously decreased therapeutic efficacy and side effects to symbiotic bacteria. Here, the authors develop a pH-responsive graphitic nanozyme that is active under low pH gastric conditions, but inactive in intestines, for selective treatment of H. pylori infections.

Published
2021

48. Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World

Author

Hirschfeld, Cole B., Shaw, Leslee J., Williams, Michelle C., Lahey, Ryan, Villines, Todd C., Dorbala, Sharmila, Choi, Andrew D., Shah, Nishant R., Bluemke, David A., Berman, Daniel S., Blankstein, Ron, Ferencik, Maros, Narula, Jagat, Winchester, David, Malkovskiy, Eli, Goebel, Benjamin, Randazzo, Michael J., Lopez-Mattei, Juan, Parwani, Purvi, Vitola, Joao V., Cerci, Rodrigo J., Better, Nathan, Raggi, Paolo, Lu, Bin, Sergienko, Vladimir, Sinitsyn, Valentin, Kudo, Takashi, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Cohen, Yosef A., Pascual, Thomas N. B., Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, Einstein, Andrew J., Cerci, Rodrigo, Hinterleitner, Gerd, Lu, Yao, Morozova, Olga, Xu, Zhuoran, Cohen, Yosef, Randazzo, Michael, Choi, Andrew, Nasery, Mohammad Nawaz, Goda, Artan, Shirka, Ervina, Benlabgaa, Rabie, Bouyoucef, Salah, Medjahedi, Abdelkader, Nailli, Qais, Agolti, Mariela, Aguero, Roberto Nicolas, Alak, Maria del Carmen, Alberguina, Lucia Graciela, Arroñada, Guillermo, Astesiano, Andrea, Astesiano, Alfredo, Norton, Carolina Bas, Benteo, Pablo, Blanco, Juan, Bonelli, Juan Manuel, Bustos, Jose Javier, Cabrejas, Raul, Cachero, Jorge, Campisi, Roxana, Canderoli, Alejandro, Carames, Silvia, Carrascosa, Patrícia, Castro, Ricardo, Cendoya, Oscar, Cognigni, Luciano Martin, Collaud, Carlos, Cortes, Claudia, Courtis, Javier, Cragnolino, Daniel, Daicz, Mariana, De La Vega, Alejandro, De Maria, Silvia Teresa, Del Riego, Horacio, Dettori, Fernando, Deviggiano, Alejandro, Dragonetti, Laura, Embon, Mario, Enriquez, Ruben Emilio, Ensinas, Jorge, Faccio, Fernando, Facello, Adolfo, Garofalo, Diego, Geronazzo, Ricardo, Gonza, Natalia, Gutierrez, Lucas, Guzzo, Miguel Angel, Hasbani, Victor, Huerin, Melina, Jäger, Victor, Lewkowicz, Julio Manuel, Nieves A López De Munaín, Maria, Lotti, Jose Maria, Marquez, Alejandra, Masoli, Osvaldo, Masoli, Osvaldo Horacio, Mastrovito, Edgardo, Mayoraz, Matias, Melado, Graciela Eva, Mele, Anibal, Merani, Maria Fernanda, Meretta, Alejandro Horacio, Molteni, Susana, Montecinos, Marcos, Noguera, Eduardo, Novoa, Carlos, Sueldo, Claudio Pereyra, Ascani, Sebastian Perez, Pollono, Pablo, Pujol, Maria Paula, Radzinschi, Alejandro, Raimondi, Gustavo, Redruello, Marcela, Rodríguez, Marina, Rodríguez, Matías, Romero, Romina Lorena, Acuña, Arturo Romero, Rovaletti, Federico, San Miguel, Lucas, Solari, Lucrecia, Strada, Bruno, Traverso, Sonia, Traverzo, Sonia Simona, Espeche, Maria del Huerto Velazquez, Weihmuller, Juan Sebastian, Wolcan, Juan, Zeffiro, Susana, Sakanyan, Mari, Beuzeville, Scott, Boktor, Raef, Butler, Patrick, Calcott, Jennifer, Carr, Loretta, Chan, Virgil, Chao, Charles, Chong, Woon, Dobson, Mark, Downie, D'Arne, Dwivedi, Girish, Elison, Barry, Engela, Jean, Francis, Roslyn, Gaikwad, Anand, Basavaraj, Ashok Gangasandra, Goodwin, Bruce, Greenough, Robert, Hamilton-Craig, Christian, Hsieh, Victar, Joshi, Subodh, Lederer, Karin, Lee, Kenneth, Lee, Joseph, Magnussen, John, Mai, Nghi, Mander, Gordon, Murton, Fiona, Nandurkar, Dee, Neill, Johanne, O'Rourke, Edward, O'Sullivan, Patricia, Pandos, George, Pathmaraj, Kunthi, Pitman, Alexander, Poulter, Rohan, Premaratne, Manuja, Prior, David, Ridley, Lloyd, Rutherford, Natalie, Salehi, Hamid, Saunders, Connor, Scarlett, Luke, Seneviratne, Sujith, Shetty, Deepa, Shrestha, Ganesh, Shulman, Jonathan, Solanki, Vijay, Stanton, Tony, Stuart, Murch, Stubbs, Michael, Swainson, Ian, Taubman, Kim, Taylor, Andrew, Thomas, Paul, Unger, Steven, Upton, Anthony, Vamadevan, Shankar, Van Gaal, William, Verjans, Johan, Voutnis, Demetrius, Wayne, Victor, Wilson, Peter, Wong, David, Wong, Kirby, Younger, John, Feuchtner, Gudrun, Mirzaei, Siroos, Weiss, Konrad, Maroz-Vadalazhskaya, Natallia, Gheysens, Olivier, Homans, Filip, Moreno-Reyes, Rodrigo, Pasquet, Agnès, Roelants, Veronique, Van De Heyning, Caroline M., Ríos, Raúl Araujo, Soldat-Stankovic, Valentina, Stankovic, Sinisa, Albernaz Siqueira, Maria Helena, Almeida, Augusto, Alves Togni, Paulo Henrique, Andrade, Jose Henrique, Andrade, Luciana, Anselmi, Carlos, Araújo, Roberta, Azevedo, Guilherme, Bezerra, Sabbrina, Biancardi, Rodrigo, Grossman, Gabriel Blacher, Brandão, Simone, Pianta, Diego Bromfman, Carreira, Lara, Castro, Bruno, Chang, Tien, Cunali, Fernando, Cury, Roberto, Dantas, Roberto, de Amorim Fernandes, Fernando, De Lorenzo, Andrea, De Macedo Filho, Robson, Erthal, Fernanda, Fernandes, Fabio, Fernandes, Juliano, De Souza, Thiago Ferreira, Alves, Wilson Furlan, Ghini, Bruno, Goncalves, Luiz, Gottlieb, Ilan, Hadlich, Marcelo, Kameoka, Vinícius, Lima, Ronaldo, Lima, Adna, Lopes, Rafael Willain, Machado e Silva, Ricardo, Magalhães, Tiago, Silva, Fábio Martins, Mastrocola, Luiz Eduardo, Medeiros, Fábio, Meneghetti, José Claudio, Naue, Vania, Naves, Danilo, Nolasco, Roberto, Nomura, Cesar, Oliveira, Joao Bruno, Paixao, Eduardo, De Carvalho, Filipe Penna, Pinto, Ibraim, Possetti, Priscila, Quinta, Mayra, Nogueira Ramos, Rodrigo Rizzo, Rocha, Ricardo, Rodrigues, Alfredo, Rodrigues, Carlos, Romantini, Leila, Sanches, Adelina, Santana, Sara, Sara da Silva, Leonardo, Schvartzman, Paulo, Matushita, Cristina Sebastião, Senra, Tiago, Shiozaki, Afonso, Menezes de Siqueira, Maria Eduarda, Siqueira, Cristiano, Smanio, Paola, Soares, Carlos Eduardo, Junior, José Soares, Bittencourt, Marcio Sommer, Spiro, Bernardo, Mesquita, Cláudio Tinoco, Torreao, Jorge, Torres, Rafael, Uellendahl, Marly, Monte, Guilherme Urpia, Veríssimo, Otávia, Cabeda, Estevan Vieira, Pedras, Felipe Villela, Waltrick, Roberto, Zapparoli, Marcello, Naseer, Hamid, Garcheva-Tsacheva, Marina, Kostadinova, Irena, Theng, Youdaline, Abikhzer, Gad, Barette, Rene, Chow, Benjamin, Dabreo, Dominique, Friedrich, Matthias, Garg, Ria, Hafez, Mohammed Nassoh, Johnson, Chris, Kiess, Marla, Leipsic, Jonathon, Leung, Eugene, Miller, Robert, Oikonomou, Anastasia, Probst, Stephan, Roifman, Idan, Small, Gary, Tandon, Vikas, Trivedi, Adwait, White, James, Zukotynski, Katherine, Canessa, Jose, Muñoz, Gabriel Castro, Concha, Carmen, Hidalgo, Pablo, Lovera, Cesar, Massardo, Teresa, Vargas, Luis Salazar, Abad, Pedro, Arturo, Harold, Ayala, Sandra, Benitez, Luis, Cadena, Alberto, Caicedo, Carlos, Moncayo, Antonio Calderón, Gomez, Sharon, Gutierrez Villamil, Claudia T., Jaimes, Claudia, Londoño, Juan, Londoño Blair, Juan Luis, Pabon, Luz, Pineda, Mauricio, Rojas, Juan Carlos, Ruiz, Diego, Escobar, Manuel Valencia, Vasquez, Andres, Vergel, Damiana, Zuluaga, Alejandro, Gamboa, Isabel Berrocal, Castro, Gabriel, González, Ulises, Baric, Ana, Batinic, Tonci, Franceschi, Maja, Paar, Maja Hrabak, Jukic, Mladen, Medakovic, Petar, Persic, Viktor, Prpic, Marina, Punda, Ante, Batista, Juan Felipe, Gómez Lauchy, Juan Manuel, Gutierrez, Yamile Marcos, Menéndez, Rayner, Peix, Amalia, Rochela, Luis, Panagidis, Christoforos, Petrou, Ioannis, Engelmann, Vaclav, Kaminek, Milan, Kincl, Vladimír, Lang, Otto, Simanek, Milan, Abdulla, Jawdat, Bøttcher, Morten, Christensen, Mette, Gormsen, Lars Christian, Hasbak, Philip, Hess, Søren, Holdgaard, Paw, Johansen, Allan, Kyhl, Kasper, Norgaard, Bjarne Linde, Øvrehus, Kristian Altern, Rønnow Sand, Niels Peter, Steffensen, Rolf, Thomassen, Anders, Zerahn, Bo, Perez, Alfredo, Escorza Velez, Giovanni Alejandro, Velez, Mayra Sanchez, Abdel Aziz, Islam Shawky, Abougabal, Mahasen, Ahmed, Taghreed, Allam, Adel, Asfour, Ahmed, Hassan, Mona, Hassan, Alia, Ibrahim, Ahmed, Kaffas, Sameh, Kandeel, Ahmed, Ali, Mohamed Mandour, Mansy, Ahmad, Maurice, Hany, Nabil, Sherif, Shaaban, Mahmoud, Flores, Ana Camila, Poksi, Anne, Knuuti, Juhani, Kokkonen, Velipekka, Larikka, Martti, Uusitalo, Valtteri, Bailly, Matthieu, Burg, Samuel, Deux, Jean-François, Habouzit, Vincent, Hyafil, Fabien, Lairez, Olivier, Proffit, Franck, Regaieg, Hamza, Sarda-Mantel, Laure, Tacher, Vania, Schneider, Roman P., Ayetey, Harold, Angelidis, George, Archontaki, Aikaterini, Chatziioannou, Sofia, Datseris, Ioannis, Fragkaki, Christina, Georgoulias, Panagiotis, Koukouraki, Sophia, Koutelou, Maria, Kyrozi, Eleni, Repasos, Evangelos, Stavrou, Petros, Valsamaki, Pipitsa, Gonzalez, Carla, Gutierrez, Goleat, Maldonado, Alejandro, Buga, Klara, Garai, Ildiko, Schmidt, Erzsébet, Szilveszter, Balint, Várady, Edit, Banthia, Nilesh, Bhagat, Jinendra Kumar, Bhargava, Rishi, Bhat, Vivek, Bhatia, Mona, Choudhury, Partha, Chowdekar, Vijay Sai, Irodi, Aparna, Jain, Shashank, Joseph, Elizabeth, Kumar, Sukriti, Girijanandan Mahapatra, Prof Dr, Mitra, Deepanjan, Mittal, Bhagwant Rai, Ozair, Ahmad, Patel, Chetan, Patel, Tapan, Patel, Ravi, Patel, Shivani, Saxena, Sudhir, Sengupta, Shantanu, Singh, Santosh, Singh, Bhanupriya, Sood, Ashwani, Verma, Atul, Affandi, Erwin, Alam Edison, Padma Savenadia, Gunawan, Gani, Hapkido, Habusari, Hidayat, Basuki, Huda, Aulia, Mukti, Anggoro Praja, Prawiro, Djoko, Soeriadi, Erwin Affandi, Syawaluddin, Hilman, Albadr, Amjed, Assadi, Majid, Emami, Farshad, Houshmand, Golnaz, Maleki, Majid, Rostami, Maryam Tajik, Zakavi, Seyed Rasoul, Zaid, Eed Abu, Agranovich, Svetlana, Arnson, Yoav, Bar-Shalom, Rachel, Frenkel, Alex, Knafo, Galit, Lugassi, Rachel, Maor Moalem, Israel Shlomo, Mor, Maya, Muskal, Noam, Ranser, Sara, Shalev, Aryeh, Albano, Domenico, Alongi, Pierpaolo, Arnone, Gaspare, Bagatin, Elisa, Baldari, Sergio, Bauckneht, Matteo, Bertelli, Paolo, Bianco, Francesco, Bonfiglioli, Rachele, Boni, Roberto, Bruno, Andrea, Bruno, Isabella, Busnardo, Elena, Califaretti, Elena, Camoni, Luca, Carnevale, Aldo, Casoni, Roberta, Cavallo, Armando Ugo, Cavenaghi, Giorgio, Chierichetti, Franca, Chiocchi, Marcello, Cittanti, Corrado, Colletta, Mauro, Conti, Umberto, Cossu, Alberto, Cuocolo, Alberto, Cuzzocrea, Marco, De Rimini, Maria Luisa, De Vincentis, Giuseppe, Del Giudice, Eleonora, Del Torto, Alberico, Della Tommasina, Veronica, Durmo, Rexhep, Erba, Paola Anna, Evangelista, Laura, Faletti, Riccardo, Faragasso, Evelina, Farsad, Mohsen, Ferro, Paola, Florimonte, Luigia, Frantellizzi, Viviana, Fringuelli, Fabio Massimo, Gatti, Marco, Gaudiano, Angela, Gimelli, Alessia, Giubbini, Raffaele, Giuffrida, Francesca, Ialuna, Salvatore, Laudicella, Riccardo, Leccisotti, Lucia, Leva, Lucia, Liga, Riccardo, Liguori, Carlo, Longo, Giampiero, Maffione, Margherita, Mancini, Maria Elisabetta, Marcassa, Claudio, Milan, Elisa, Nardi, Barbara, Pacella, Sara, Pepe, Giovanna, Pontone, Gianluca, Pulizzi, Sabina, Quartuccio, Natale, Rampin, Lucia, Ricci, Fabrizio, Rossini, Pierluigi, Rubini, Giuseppe, Russo, Vincenzo, Sacchetti, Gian Mauro, Sambuceti, Gianmario, Scarano, Massimo, Sciagrà, Roberto, Sperandio, Massimiliano, Stefanelli, Antonella, Ventroni, Guido, Zoboli, Stefania, Baugh, Dainia, Chambers, Duane, Madu, Ernest, Nunura, Felix, Asano, Hiroshi, Chimura, Chimura Misato, Fujimoto, Shinichiro, Fujisue, Koichiro, Fukunaga, Tomohisa, Fukushima, Yoshimitsu, Fukuyama, Kae, Hashimoto, Jun, Ichikawa, Yasutaka, Iguchi, Nobuo, Imai, Masamichi, Inaki, Anri, Ishimura, Hayato, Isobe, Satoshi, Kadokami, Toshiaki, Kato, Takao, Kumita, Shinichiro, Maruno, Hirotaka, Mataki, Hiroyuki, Miyagawa, Masao, Morimoto, Ryota, Moroi, Masao, Nagamachi, Shigeki, Nakajima, Kenichi, Nakata, Tomoaki, Nakazato, Ryo, Nanasato, Mamoru, Naya, Masanao, Norikane, Takashi, Ohta, Yasutoshi, Okayama, Satoshi, Okizaki, Atsutaka, Otomi, Yoichi, Otsuka, Hideki, Saito, Masaki, Sakata, Sakata Yasushi, Sarai, Masayoshi, Sato, Daisuke, Shiraishi, Shinya, Suwa, Yoshinobu, Takanami, Kentaro, Takehana, Kazuya, Taki, Junichi, Tamaki, Nagara, Taniguchi, Yasuyo, Teragawa, Hiroki, Tomizawa, Nobuo, Tsujita, Kenichi, Umeji, Kyoko, Wakabayashi, Yasushi, Yamada, Shinichiro, Yamazaki, Shinya, Yoneyama, Tatsuya, Rawashdeh, Mohammad, Batyrkhanov, Daultai, Dautov, Tairkhan, Makhdomi, Khalid, Ombati, Kevin, Alkandari, Faridah, Garashi, Masoud, Coie, Tchoyoson Lim, Rajvong, Sonexay, Kalinin, Artem, Kalnina, Marika, Haidar, Mohamad, Komiagiene, Renata, Kviecinskiene, Giedre, Mataciunas, Mindaugas, Vajauskas, Donatas, Picard, Christian, Karim, Noor Khairiah A., Reichmuth, Luise, Samuel, Anthony, Allarakha, Mohammad Aaftaab, Naojee, Ambedhkar Shantaram, Alexanderson-Rosas, Erick, Barragan, Erika, González-Montecinos, Alejandro Becerril, Cabada, Manuel, Rodriguez, Daniel Calderon, Carvajal-Juarez, Isabel, Cortés, Violeta, Cortés, Filiberto, De La Peña, Erasmo, Gama-Moreno, Manlio, González, Luis, Ramírez, Nelsy Gonzalez, Jiménez-Santos, Moisés, Matos, Luis, Monroy, Edgar, Morelos, Martha, Ornelas, Mario, Ortga Ramirez, Jose Alberto, Preciado-Anaya, Andrés, Preciado-Gutiérrez, Óscar Ulises, Barragan, Adriana Puente, Rosales Uvera, Sandra Graciela, Sandoval, Sigelinda, Tomas, 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Al-Bulushi, Naeema, Jawa, Zabah, Tag, Naima, Afzal, Muhammad Shehzad, Fatima, Shazia, Younis, Muhammad Numair, Riaz, Musab, Saadullah, Mohammad, Herrera, Yariela, Lenturut-Katal, Dora, Vázquez, Manuel Castillo, Ortellado, José, Akhter, Afroza, Cao, Dianbo, Cheung, Stephen, Dai, Xu, Gong, Lianggeng, Han, Dan, Hou, Yang, Li, Caiying, Li, Tao, Li, Dong, Li, Sijin, Liu, Jinkang, Liu, Hui, Ng, Ming Yen, Sun, Kai, Tang, Gongshun, Wang, Jian, Wang, Ximing, Wang, Zhao-Qian, Wang, Yining, Wang, Yifan, Wu, Jiang, Wu, Zhifang, Xia, Liming, Xiao, Jiangxi, Xu, Lei, Yang, Youyou, Yin, Wu, Yu, Jianqun, Yuan, Li, Zhang, Tong, Zhang, Longjiang, Zhang, Yong-Gao, Zhang, Xiaoli, Zhu, Li, Alfaro, Ana, Abrihan, Paz, Barroso, Asela, Cruz, Eric, Gomez, Marie Rhiamar, Magboo, Vincent Peter, Medina, John Michael, Obaldo, Jerry, Pastrana, Davidson, Pawhay, Christian Michael, Quinon, Alvin, Tang, Jeanelle Margareth, Tecson, Bettina, Uson, Kristine Joy, Uy, Mila, Kostkiewicz, Magdalena, Kunikowska, Jolanta, 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Saranovic, Dragana Sobic, Keng, Felix, Jason See, Jia Hao, Sekar, Ramkumar, Yew, Min Sen, Vondrak, Andrej, Bejai, Shereen, Bennie, George, Bester, Ria, Engelbrecht, Gerrit, Evbuomwan, Osayande, Gongxeka, Harlem, Vuuren, Magritha Jv, Kaplan, Mitchell, Khushica, Purbhoo, Lakhi, Hoosen, Louw, Lizette, Malan, Nico, Milos, Katarina, Modiselle, Moshe, More, Stuart, Naidoo, Mathava, Scholtz, Leonie, Vangu, Mboyo, Aguadé-Bruix, Santiago, Blanco, Isabel, Cabrera, Antonio, Camarero, Alicia, Casáns-Tormo, Irene, Cuellar-Calabria, Hug, Flotats, Albert, Fuentes Cañamero, Maria Eugenia, García, María Elia, Jimenez-Heffernan, Amelia, Leta, Rubén, Diaz, Javier Lopez, Lumbreras, Luis, Marquez-Cabeza, Juan Javier, Martin, Francisco, Martinez de Alegria, Anxo, Medina, Francisco, Canal, Maria Pedrera, Peiro, Virginia, Pubul-Nuñez, Virginia, Rayo Madrid, Juan Ignacio, Rey, Cristina Rodríguez, Perez, Ricardo Ruano, Ruiz, Joaquín, Hernández, Gertrudis Sabatel, Sevilla, Ana, Zeidán, Nahla, Nanayakkara, 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Kitt, Jamie, Lee, Ken, Low, Chen, Mak, Sze Mun, Marousa, Ntouskou, Martin, Jon, Mcalindon, Elisa, Menezes, Leon, Morgan-Hughes, Gareth, Moss, Alastair, Murray, Anthony, Nicol, Edward, Patel, Dilip, Peebles, Charles, Pugliese, Francesca, Luis Rodrigues, Jonathan Carl, Rofe, Christopher, Sabharwal, Nikant, Schofield, Rebecca, Semple, Thomas, Sharma, Naveen, Strouhal, Peter, Subedi, Deepak, Topping, William, Tweed, Katharine, Weir-Mccall, Jonathan, Abbara, Suhny, Abbasi, Taimur, Abbott, Brian, Abohashem, Shady, Abramson, Sandra, Al-Abboud, Tarek, Al-Mallah, Mouaz, Almousalli, Omar, Ananthasubramaniam, Karthikeyan, Kumar, Mohan Ashok, Askew, Jeffrey, Attanasio, Lea, Balmer-Swain, Mallory, Bayer, Richard R., Bernheim, Adam, Bhatti, Sabha, Bieging, Erik, Bloom, Stephen, Blue, Sean, Bluemke, David, Borges, Andressa, Branch, Kelley, Bravo, Paco, Brothers, Jessica, Budoff, Matthew, Bullock-Palmer, Renée, Burandt, Angela, Burke, Floyd W., Bush, Kelvin, Candela, Candace, Capasso, Elizabeth, 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George Kinzfogl, Kircher, Jacqueline, Kirkbride, Rachael, Kontos, Michael, Kottam, Anupama, Krepp, Joseph, Layer, Jay, Lee, Steven H., Leppo, Jeffrey, Lesser, John, Leung, Steve, Lewin, Howard, Litmanovich, Diana, Liu, Yiyan, Magurany, Kathleen, Markowitz, Jeremy, Marn, Amanda, Matis, Stephen E., Mckenna, Michael, Mcrae, Tony, Mendoza, Fernando, Merhige, Michael, Min, David, Moffitt, Chanan, Moncher, Karen, Moore, Warren, Morayati, Shamil, Morris, Michael, Mossa-Basha, Mahmud, Mrsic, Zorana, Murthy, Venkatesh, Nagpal, Prashant, Napier, Kyle, Nelson, Katarina, Nijjar, Prabhjot, Osman, Medhat, Passen, Edward, Patel, Amit, Patil, Pravin, Paul, Ryan, Phillips, Lawrence, Polsani, Venkateshwar, Poludasu, Rajaram, Pomerantz, Brian, Porter, Thomas, Prentice, Ryan, Pursnani, Amit, Rabbat, Mark, Ramamurti, Suresh, Rich, Florence, Luna, Hiram Rivera, Robinson, Austin, Robles, Kim, Rodríguez, Cesar, Rorie, Mark, Rumberger, John, Russell, Raymond, Sabra, Philip, Sadler, Diego, Schemmer, Mary, Schoepf, U. 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Jorge, Faccio, Fernando, Facello, Adolfo, Garofalo, Diego, Geronazzo, Ricardo, Gonza, Natalia, Gutierrez, Luca, Guzzo, Miguel Angel, Hasbani, Victor, Huerin, Melina, Jäger, Victor, Lewkowicz, Julio Manuel, Nieves A López De Munaín, Maria, Lotti, Jose Maria, Marquez, Alejandra, Masoli, Osvaldo, Masoli, Osvaldo Horacio, Mastrovito, Edgardo, Mayoraz, Matia, Melado, Graciela Eva, Mele, Anibal, Merani, Maria Fernanda, Meretta, Alejandro Horacio, Molteni, Susana, Montecinos, Marco, Noguera, Eduardo, Novoa, Carlo, Sueldo, Claudio Pereyra, Ascani, Sebastian Perez, Pollono, Pablo, Pujol, Maria Paula, Radzinschi, Alejandro, Raimondi, Gustavo, Redruello, Marcela, Rodríguez, Marina, Rodríguez, Matía, Romero, Romina Lorena, Acuña, Arturo Romero, Rovaletti, Federico, San Miguel, Luca, Solari, Lucrecia, Strada, Bruno, Traverso, Sonia, Traverzo, Sonia Simona, Espeche, Maria del Huerto Velazquez, Weihmuller, Juan Sebastian, Wolcan, Juan, Zeffiro, Susana, Sakanyan, Mari, Beuzeville, Scott, Boktor, Raef, Butler, Patrick, Calcott, Jennifer, Carr, Loretta, Chan, Virgil, Chao, Charle, Chong, Woon, Dobson, Mark, Downie, D'Arne, Dwivedi, Girish, Elison, Barry, Engela, Jean, Francis, Roslyn, Gaikwad, Anand, Basavaraj, Ashok Gangasandra, Goodwin, Bruce, Greenough, Robert, Hamilton-Craig, Christian, Hsieh, Victar, Joshi, Subodh, Lederer, Karin, Lee, Kenneth, Lee, Joseph, Magnussen, John, Mai, Nghi, Mander, Gordon, Murton, Fiona, Nandurkar, Dee, Neill, Johanne, O'Rourke, Edward, O'Sullivan, Patricia, Pandos, George, Pathmaraj, Kunthi, Pitman, Alexander, Poulter, Rohan, Premaratne, Manuja, Prior, David, Ridley, Lloyd, Rutherford, Natalie, Salehi, Hamid, Saunders, Connor, Scarlett, Luke, Seneviratne, Sujith, Shetty, Deepa, Shrestha, Ganesh, Shulman, Jonathan, Solanki, Vijay, Stanton, Tony, Stuart, Murch, Stubbs, Michael, Swainson, Ian, Taubman, Kim, Taylor, Andrew, Thomas, Paul, Unger, Steven, Upton, Anthony, Vamadevan, Shankar, Van Gaal, William, Verjans, Johan, Voutnis, Demetriu, Wayne, Victor, Wilson, Peter, Wong, David, Wong, Kirby, Younger, John, Feuchtner, Gudrun, Mirzaei, Siroo, Weiss, Konrad, Maroz-Vadalazhskaya, Natallia, Gheysens, Olivier, Homans, Filip, Moreno-Reyes, Rodrigo, Pasquet, Agnè, Roelants, Veronique, Van De Heyning, Caroline M., Ríos, Raúl Araujo, Soldat-Stankovic, Valentina, Stankovic, Sinisa, Albernaz Siqueira, Maria Helena, Almeida, Augusto, Alves Togni, Paulo Henrique, Andrade, Jose Henrique, Andrade, Luciana, Anselmi, Carlo, Araújo, Roberta, Azevedo, Guilherme, Bezerra, Sabbrina, Biancardi, Rodrigo, Grossman, Gabriel Blacher, Brandão, Simone, Pianta, Diego Bromfman, Carreira, Lara, Castro, Bruno, Chang, Tien, Cunali, Fernando, Cury, Roberto, Dantas, Roberto, de Amorim Fernandes, Fernando, De Lorenzo, Andrea, De Macedo Filho, Robson, Erthal, Fernanda, Fernandes, Fabio, Fernandes, Juliano, De Souza, Thiago Ferreira, Alves, Wilson Furlan, Ghini, Bruno, Goncalves, Luiz, Gottlieb, Ilan, Hadlich, Marcelo, Kameoka, Viníciu, Lima, Ronaldo, Lima, Adna, Lopes, Rafael Willain, Machado e Silva, Ricardo, Magalhães, Tiago, Silva, Fábio Martin, Mastrocola, Luiz Eduardo, Medeiros, Fábio, Meneghetti, José Claudio, Naue, Vania, Naves, Danilo, Nolasco, Roberto, Nomura, Cesar, Oliveira, Joao Bruno, Paixao, Eduardo, De Carvalho, Filipe Penna, Pinto, Ibraim, Possetti, Priscila, Quinta, Mayra, Nogueira Ramos, Rodrigo Rizzo, Rocha, Ricardo, Rodrigues, Alfredo, Rodrigues, Carlo, Romantini, Leila, Sanches, Adelina, Santana, Sara, Sara da Silva, Leonardo, Schvartzman, Paulo, Matushita, Cristina Sebastião, Senra, Tiago, Shiozaki, Afonso, Menezes de Siqueira, Maria Eduarda, Siqueira, Cristiano, Smanio, Paola, Soares, Carlos Eduardo, Junior, José Soare, Bittencourt, Marcio Sommer, Spiro, Bernardo, Mesquita, Cláudio Tinoco, Torreao, Jorge, Torres, Rafael, Uellendahl, Marly, Monte, Guilherme Urpia, Veríssimo, Otávia, Cabeda, Estevan Vieira, Pedras, Felipe Villela, Waltrick, Roberto, Zapparoli, Marcello, Naseer, Hamid, Garcheva-Tsacheva, Marina, Kostadinova, Irena, Theng, Youdaline, Abikhzer, Gad, Barette, Rene, Chow, Benjamin, Dabreo, Dominique, Friedrich, Matthia, Garg, Ria, Hafez, Mohammed Nassoh, Johnson, Chri, Kiess, Marla, Leipsic, Jonathon, Leung, Eugene, Miller, Robert, Oikonomou, Anastasia, Probst, Stephan, Roifman, Idan, Small, Gary, Tandon, Vika, Trivedi, Adwait, White, Jame, Zukotynski, Katherine, Canessa, Jose, Muñoz, Gabriel Castro, Concha, Carmen, Hidalgo, Pablo, Lovera, Cesar, Massardo, Teresa, Vargas, Luis Salazar, Abad, Pedro, Arturo, Harold, Ayala, Sandra, Benitez, Lui, Cadena, Alberto, Caicedo, Carlo, Moncayo, Antonio Calderón, Gomez, Sharon, Gutierrez Villamil, Claudia T., Jaimes, Claudia, Londoño, Juan, Londoño Blair, Juan Lui, Pabon, Luz, Pineda, Mauricio, Rojas, Juan Carlo, Ruiz, Diego, Escobar, Manuel Valencia, Vasquez, Andre, Vergel, Damiana, Zuluaga, Alejandro, Gamboa, Isabel Berrocal, Castro, Gabriel, González, Ulise, Baric, Ana, Batinic, Tonci, Franceschi, Maja, Paar, Maja Hrabak, Jukic, Mladen, Medakovic, Petar, Persic, Viktor, Prpic, Marina, Punda, Ante, Batista, Juan Felipe, Gómez Lauchy, Juan Manuel, Gutierrez, Yamile Marco, Menéndez, Rayner, Peix, Amalia, Rochela, Lui, Panagidis, Christoforo, Petrou, Ioanni, Engelmann, Vaclav, Kaminek, Milan, Kincl, Vladimír, Lang, Otto, Simanek, Milan, Abdulla, Jawdat, Bøttcher, Morten, Christensen, Mette, Gormsen, Lars Christian, Hasbak, Philip, Hess, Søren, Holdgaard, Paw, Johansen, Allan, Kyhl, Kasper, Norgaard, Bjarne Linde, Øvrehus, Kristian Altern, Rønnow Sand, Niels Peter, Steffensen, Rolf, Thomassen, Ander, Zerahn, Bo, Perez, Alfredo, Escorza Velez, Giovanni Alejandro, Velez, Mayra Sanchez, Abdel Aziz, Islam Shawky, Abougabal, Mahasen, Ahmed, Taghreed, Allam, Adel, Asfour, Ahmed, Hassan, Mona, Hassan, Alia, Ibrahim, Ahmed, Kaffas, Sameh, Kandeel, Ahmed, Ali, Mohamed Mandour, Mansy, Ahmad, Maurice, Hany, Nabil, Sherif, Shaaban, Mahmoud, Flores, Ana Camila, Poksi, Anne, Knuuti, Juhani, Kokkonen, Velipekka, Larikka, Martti, Uusitalo, Valtteri, Bailly, Matthieu, Burg, Samuel, Deux, Jean-Françoi, Habouzit, Vincent, Hyafil, Fabien, Lairez, Olivier, Proffit, Franck, Regaieg, Hamza, Sarda-Mantel, Laure, Tacher, Vania, Schneider, Roman P., Ayetey, Harold, Angelidis, George, Archontaki, Aikaterini, Chatziioannou, Sofia, Datseris, Ioanni, Fragkaki, Christina, Georgoulias, Panagioti, Koukouraki, Sophia, Koutelou, Maria, Kyrozi, Eleni, Repasos, Evangelo, Stavrou, Petro, Valsamaki, Pipitsa, Gonzalez, Carla, Gutierrez, Goleat, Maldonado, Alejandro, Buga, Klara, Garai, Ildiko, Schmidt, Erzsébet, Szilveszter, Balint, Várady, Edit, Banthia, Nilesh, Bhagat, Jinendra Kumar, Bhargava, Rishi, Bhat, Vivek, Bhatia, Mona, Choudhury, Partha, Chowdekar, Vijay Sai, Irodi, Aparna, Jain, Shashank, Joseph, Elizabeth, Kumar, Sukriti, Girijanandan Mahapatra, Prof Dr, Mitra, Deepanjan, Mittal, Bhagwant Rai, Ozair, Ahmad, Patel, Chetan, Patel, Tapan, Patel, Ravi, Patel, Shivani, Saxena, Sudhir, Sengupta, Shantanu, Singh, Santosh, Singh, Bhanupriya, Sood, Ashwani, Verma, Atul, Affandi, Erwin, Alam, Edison, Padma, Savenadia, Gunawan, Gani, Hapkido, Habusari, Hidayat, Basuki, Huda, Aulia, Mukti, Anggoro Praja, Prawiro, Djoko, Soeriadi, Erwin Affandi, Syawaluddin, Hilman, Albadr, Amjed, Assadi, Majid, Emami, Farshad, Houshmand, Golnaz, Maleki, Majid, Rostami, Maryam Tajik, Zakavi, Seyed Rasoul, Zaid, Eed Abu, Agranovich, Svetlana, Arnson, Yoav, Bar-Shalom, Rachel, Frenkel, Alex, Knafo, Galit, Lugassi, Rachel, Maor Moalem, Israel Shlomo, Mor, Maya, Muskal, Noam, Ranser, Sara, Shalev, Aryeh, Albano, Domenico, Alongi, Pierpaolo, Arnone, Gaspare, Bagatin, Elisa, Baldari, Sergio, Bauckneht, Matteo, Bertelli, Paolo, Bianco, Francesco, Bonfiglioli, Rachele, Boni, Roberto, Bruno, Andrea, Bruno, Isabella, Busnardo, Elena, Califaretti, Elena, Camoni, Luca, Carnevale, Aldo, Casoni, Roberta, Cavallo, Armando Ugo, Cavenaghi, Giorgio, Chierichetti, Franca, Chiocchi, Marcello, Cittanti, Corrado, Colletta, Mauro, Conti, Umberto, Cossu, Alberto, Cuocolo, Alberto, Cuzzocrea, Marco, De Rimini, Maria Luisa, De Vincentis, Giuseppe, Del Giudice, Eleonora, Del Torto, Alberico, Della Tommasina, Veronica, Durmo, Rexhep, Erba, Paola Anna, Evangelista, Laura, Faletti, Riccardo, Faragasso, Evelina, Farsad, Mohsen, Ferro, Paola, Florimonte, Luigia, Frantellizzi, Viviana, Fringuelli, Fabio Massimo, Gatti, Marco, Gaudiano, Angela, Gimelli, Alessia, Giubbini, Raffaele, Giuffrida, Francesca, Ialuna, Salvatore, Laudicella, Riccardo, Leccisotti, Lucia, Leva, Lucia, Liga, Riccardo, Liguori, Carlo, Longo, Giampiero, Maffione, Margherita, Mancini, Maria Elisabetta, Marcassa, Claudio, Milan, Elisa, Nardi, Barbara, Pacella, Sara, Pepe, Giovanna, Pontone, Gianluca, Pulizzi, Sabina, Quartuccio, Natale, Rampin, Lucia, Ricci, Fabrizio, Rossini, Pierluigi, Rubini, Giuseppe, Russo, Vincenzo, Sacchetti, Gian Mauro, Sambuceti, Gianmario, Scarano, Massimo, Sciagrà, Roberto, Sperandio, Massimiliano, Stefanelli, Antonella, Ventroni, Guido, Zoboli, Stefania, Baugh, Dainia, Chambers, Duane, Madu, Ernest, Nunura, Felix, Asano, Hiroshi, Chimura, Chimura Misato, Fujimoto, Shinichiro, Fujisue, Koichiro, Fukunaga, Tomohisa, Fukushima, Yoshimitsu, Fukuyama, Kae, Hashimoto, Jun, Ichikawa, Yasutaka, Iguchi, Nobuo, Imai, Masamichi, Inaki, Anri, Ishimura, Hayato, Isobe, Satoshi, Kadokami, Toshiaki, Kato, Takao, Kumita, Shinichiro, Maruno, Hirotaka, Mataki, Hiroyuki, Miyagawa, Masao, Morimoto, Ryota, Moroi, Masao, Nagamachi, Shigeki, Nakajima, Kenichi, Nakata, Tomoaki, Nakazato, Ryo, Nanasato, Mamoru, Naya, Masanao, Norikane, Takashi, Ohta, Yasutoshi, Okayama, Satoshi, Okizaki, Atsutaka, Otomi, Yoichi, Otsuka, Hideki, Saito, Masaki, Sakata, Sakata Yasushi, Sarai, Masayoshi, Sato, Daisuke, Shiraishi, Shinya, Suwa, Yoshinobu, Takanami, Kentaro, Takehana, Kazuya, Taki, Junichi, Tamaki, Nagara, Taniguchi, Yasuyo, Teragawa, Hiroki, Tomizawa, Nobuo, Tsujita, Kenichi, Umeji, Kyoko, Wakabayashi, Yasushi, Yamada, Shinichiro, Yamazaki, Shinya, Yoneyama, Tatsuya, Rawashdeh, Mohammad, Batyrkhanov, Daultai, Dautov, Tairkhan, Makhdomi, Khalid, Ombati, Kevin, Alkandari, Faridah, Garashi, Masoud, Coie, Tchoyoson Lim, Rajvong, Sonexay, Kalinin, Artem, Kalnina, Marika, Haidar, Mohamad, Komiagiene, Renata, Kviecinskiene, Giedre, Mataciunas, Mindauga, Vajauskas, Donata, Picard, Christian, Karim, Noor Khairiah A., Reichmuth, Luise, Samuel, Anthony, Allarakha, Mohammad Aaftaab, Naojee, Ambedhkar Shantaram, Alexanderson-Rosas, Erick, Barragan, Erika, González-Montecinos, Alejandro Becerril, Cabada, Manuel, Rodriguez, Daniel Calderon, Carvajal-Juarez, Isabel, Cortés, Violeta, Cortés, Filiberto, De La Peña, Erasmo, Gama-Moreno, Manlio, González, Lui, Ramírez, Nelsy Gonzalez, Jiménez-Santos, Moisé, Matos, Lui, Monroy, Edgar, Morelos, Martha, Ornelas, Mario, Ortga Ramirez, Jose Alberto, Preciado-Anaya, André, Preciado-Gutiérrez, Óscar Ulise, Barragan, Adriana Puente, Rosales Uvera, Sandra Graciela, Sandoval, Sigelinda, Tomas, Miguel Santaularia, Sierra-Galan, Lilia M., Siu, Silvia, Vallejo, Enrique, Valles, Mario, Faraggi, Marc, Sereegotov, Erdenechimeg, Ilic, Srdja, Ben-Rais, Nozha, Alaoui, Nadia Ismaili, Taleb, Sara, Myo, Khin Pa, Thu, Phyo Si, Ghimire, Ram Kumar, Rajbanshi, Bijoy, Barneveld, Peter, Glaudemans, Andor, Habets, Jesse, Koopmans, Klaas Pieter, Manders, Jeroen, Pool, Stefan, Scholte, Arthur, Scholtens, Asbjørn, Slart, Riemer, Thimister, Paul, Van Asperen, Erik-Jan, Veltman, Niel, Verschure, Derk, Wagenaar, Nil, Edmond, John, Ellis, Chri, Johnson, Kerryanne, Keenan, Ro, Hua, Shaw, Occleshaw, Christopher, Sasse, Alexander, To, Andrew, Van Pelt, Niel, Young, Calum, Cuadra, Teresa, Roque Vanegas, Hector Bladimir, Soli, Idrissa Adamou, Issoufou, Djibrillou Moussa, Ayodele, Tolulope, Madu, Chibuzo, Onimode, Yetunde, Efros-Monsen, Elen, Forsdahl, Signe Helene, Hildre Dimmen, Jenni-Mari, Jørgensen, Arve, Krohn, Isabel, Løvhaugen, Pål, Bråten, Anders Tjellaug, Al Dhuhli, Humoud, Al Kindi, Faiza, Al-Bulushi, Naeema, Jawa, Zabah, Tag, Naima, Afzal, Muhammad Shehzad, Fatima, Shazia, Younis, Muhammad Numair, Riaz, Musab, Saadullah, Mohammad, Herrera, Yariela, Lenturut-Katal, Dora, Vázquez, Manuel Castillo, Ortellado, José, Akhter, Afroza, Cao, Dianbo, Cheung, Stephen, Dai, Xu, Gong, Lianggeng, Han, Dan, Hou, Yang, Li, Caiying, Li, Tao, Li, Dong, Li, Sijin, Liu, Jinkang, Liu, Hui, Ng, Ming Yen, Sun, Kai, Tang, Gongshun, Wang, Jian, Wang, Ximing, Wang, Zhao-Qian, Wang, Yining, Wang, Yifan, Wu, Jiang, Wu, Zhifang, Xia, Liming, Xiao, Jiangxi, Xu, Lei, Yang, Youyou, Yin, Wu, Yu, Jianqun, Yuan, Li, Zhang, Tong, Zhang, Longjiang, Zhang, Yong-Gao, Zhang, Xiaoli, Zhu, Li, Alfaro, Ana, Abrihan, Paz, Barroso, Asela, Cruz, Eric, Gomez, Marie Rhiamar, Magboo, Vincent Peter, Medina, John Michael, Obaldo, Jerry, Pastrana, Davidson, Pawhay, Christian Michael, Quinon, Alvin, Tang, Jeanelle Margareth, Tecson, Bettina, Uson, Kristine Joy, Uy, Mila, Kostkiewicz, Magdalena, Kunikowska, Jolanta, Bettencourt, Nuno, Cantinho, Guilhermina, Ferreira, Antonio, Syed, Ghulam, Arnous, Samer, Atyani, Said, Byrne, Angela, Gleeson, Tadhg, Kerins, David, Meehan, Conor, Murphy, David, Murphy, Mark, Murray, John, O'Brien, Julie, Bang, Ji-In, Bom, Henry, Cho, Sang-Geon, Hong, Chae Moon, Jang, Su Jin, Jeong, Yong Hyu, Kang, Won Jun, Kim, Ji-Young, Lee, Jaetae, Namgung, Chang Kyeong, So, Young, Won, Kyoung Sook, Majstorov, Venjamin, Vavlukis, Marija, Salobir, Barbara Gužic, Štalc, Monika, Benedek, Theodora, Benedek, Imre, Mititelu, Raluca, Stan, Claudiu Adrian, Ansheles, Alexey, Dariy, Olga, Drozdova, Olga, Gagarina, Nina, Gulyaev, Vsevolod Milyevich, Itskovich, Irina, Karalkin, Anatoly, Kokov, Alexander, Migunova, Ekaterina, Pospelov, Viktor, Ryzhkova, Daria, Saifullina, Guzaliya, Sazonova, Svetlana, Shurupova, Irina, Trifonova, Tatjana, Ussov, Wladimir Yurievich, Vakhromeeva, Margarita, Valiullina, Nailya, Zavadovsky, Konstantin, Zhuravlev, Kirill, Alasnag, Mirvat, Okarvi, Subhani, Saranovic, Dragana Sobic, Keng, Felix, Jason See, Jia Hao, Sekar, Ramkumar, Yew, Min Sen, Vondrak, Andrej, Bejai, Shereen, Bennie, George, Bester, Ria, Engelbrecht, Gerrit, Evbuomwan, Osayande, Gongxeka, Harlem, Vuuren, Magritha Jv, Kaplan, Mitchell, Khushica, Purbhoo, Lakhi, Hoosen, Louw, Lizette, Malan, Nico, Milos, Katarina, Modiselle, Moshe, More, Stuart, Naidoo, Mathava, Scholtz, Leonie, Vangu, Mboyo, Aguadé-Bruix, Santiago, Blanco, Isabel, Cabrera, Antonio, Camarero, Alicia, Casáns-Tormo, Irene, Cuellar-Calabria, Hug, Flotats, Albert, Fuentes Cañamero, Maria Eugenia, García, María Elia, Jimenez-Heffernan, Amelia, Leta, Rubén, Diaz, Javier Lopez, Lumbreras, Lui, Marquez-Cabeza, Juan Javier, Martin, Francisco, Martinez de Alegria, Anxo, Medina, Francisco, Canal, Maria Pedrera, Peiro, Virginia, Pubul-Nuñez, Virginia, Rayo Madrid, Juan Ignacio, Rey, Cristina Rodríguez, Perez, Ricardo Ruano, Ruiz, Joaquín, Hernández, Gertrudis Sabatel, Sevilla, Ana, Zeidán, Nahla, Nanayakkara, Damayanthi, Udugama, Chandraguptha, Simonsson, Magnu, Alkadhi, Hatem, Buechel, Ronny Ralf, Burger, Peter, Ceriani, Luca, De Boeck, Bart, Gräni, Christoph, Juillet de Saint Lager Lucas, Alix, Kamani, Christel H., Kawel-Boehm, Nadine, Manka, Robert, Prior, John O., Rominger, Axel, Vallée, Jean-Paul, Khiewvan, Benjapa, Premprabha, Teerapon, Thientunyakit, Tanyaluck, Sellem, Ali, Kir, Kemal Metin, Sayman, Haluk, Sebikali, Mugisha Juliu, Muyinda, Zerida, Kmetyuk, Yaroslav, Korol, Pavlo, Mykhalchenko, Olena, Pliatsek, Volodymyr, Satyr, Maryna, Albalooshi, Batool, Ahmed Hassan, Mohamed Ismail, Anderson, Jill, Bedi, Punit, Biggans, Thoma, Bularga, Anda, Bull, Russell, Burgul, Rajesh, Carpenter, John-Paul, Coles, Duncan, Cusack, David, Deshpande, Aparna, Dougan, John, Fairbairn, Timothy, Farrugia, Alexia, Gopalan, Deepa, Gummow, Alistair, Ramkumar, Prasad Guntur, Hamilton, Mark, Harbinson, Mark, Hartley, Thoma, Hudson, Benjamin, Joshi, Nikhil, Kay, Michael, Kelion, Andrew, Khokhar, Azhar, Kitt, Jamie, Lee, Ken, Low, Chen, Mak, Sze Mun, Marousa, Ntouskou, Martin, Jon, Mcalindon, Elisa, Menezes, Leon, Morgan-Hughes, Gareth, Moss, Alastair, Murray, Anthony, Nicol, Edward, Patel, Dilip, Peebles, Charle, Pugliese, Francesca, Luis Rodrigues, Jonathan Carl, Rofe, Christopher, Sabharwal, Nikant, Schofield, Rebecca, Semple, Thoma, Sharma, Naveen, Strouhal, Peter, Subedi, Deepak, Topping, William, Tweed, Katharine, Weir-Mccall, Jonathan, Abbara, Suhny, Abbasi, Taimur, Abbott, Brian, Abohashem, Shady, Abramson, Sandra, Al-Abboud, Tarek, Al-Mallah, Mouaz, Almousalli, Omar, Ananthasubramaniam, Karthikeyan, Kumar, Mohan Ashok, Askew, Jeffrey, Attanasio, Lea, Balmer-Swain, Mallory, Bayer, Richard R., Bernheim, Adam, Bhatti, Sabha, Bieging, Erik, Bloom, Stephen, Blue, Sean, Bluemke, David, Borges, Andressa, Branch, Kelley, Bravo, Paco, Brothers, Jessica, Budoff, Matthew, Bullock-Palmer, Renée, Burandt, Angela, Burke, Floyd W., Bush, Kelvin, Candela, Candace, Capasso, Elizabeth, Cavalcante, Joao, Chang, Donald, Chatterjee, Saurav, Chatzizisis, Yianni, Cheezum, Michael, Chen, Tiffany, Chen, Jennifer, Chen, Marcu, Clarcq, Jame, Cordero, Ayreen, Crim, Matthew, Danciu, Sorin, Decter, Bruce, Dhruva, Nimish, Doherty, Neil, Doukky, Rami, Dunbar, Anjori, Duvall, William, Edwards, Rachael, Esquitin, Kerry, Farah, Husam, Fentanes, Emilio, Fisher, Daniel, Fitzpatrick, Daniel, Foster, Cameron, Fuisz, Tony, Gannon, Michael, Gastner, Lori, Gerson, Myron, Ghoshhajra, Brian, Goldberg, Alan, Goldner, Brian, Gonzalez, Jorge, Gore, Rosco, Gracia-López, Sandra, Hage, Fadi, Haider, Agha, Haider, Sofia, Hamirani, Yasmin, Hassen, Karen, Hatfield, Mallory, Hawkins, Carolyn, Hawthorne, Katie, Heath, Nichola, Hendel, Robert, Hernandez, Phillip, Hill, Gregory, Horgan, Stephen, Huffman, Jeff, Hurwitz, Lynne, Iskandrian, Ami, Janardhanan, Rajesh, Jellis, Christine, Jerome, Scott, Kalra, Dinesh, Kaviratne, Summanther, Kay, Fernando, Kelly, Faith, Khalique, Omar, Kinkhabwala, Mona, Iii, George Kinzfogl, Kircher, Jacqueline, Kirkbride, Rachael, Kontos, Michael, Kottam, Anupama, Krepp, Joseph, Layer, Jay, Lee, Steven H., Leppo, Jeffrey, Lesser, John, Leung, Steve, Lewin, Howard, Litmanovich, Diana, Liu, Yiyan, Magurany, Kathleen, Markowitz, Jeremy, Marn, Amanda, Matis, Stephen E., Mckenna, Michael, Mcrae, Tony, Mendoza, Fernando, Merhige, Michael, Min, David, Moffitt, Chanan, Moncher, Karen, Moore, Warren, Morayati, Shamil, Morris, Michael, Mossa-Basha, Mahmud, Mrsic, Zorana, Murthy, Venkatesh, Nagpal, Prashant, Napier, Kyle, Nelson, Katarina, Nijjar, Prabhjot, Osman, Medhat, Passen, Edward, Patel, Amit, Patil, Pravin, Paul, Ryan, Phillips, Lawrence, Polsani, Venkateshwar, Poludasu, Rajaram, Pomerantz, Brian, Porter, Thoma, Prentice, Ryan, Pursnani, Amit, Rabbat, Mark, Ramamurti, Suresh, Rich, Florence, Luna, Hiram Rivera, Robinson, Austin, Robles, Kim, Rodríguez, Cesar, Rorie, Mark, Rumberger, John, Russell, Raymond, Sabra, Philip, Sadler, Diego, Schemmer, Mary, Schoepf, U. Joseph, Shah, Samir, Shah, Nishant, Shanbhag, Sujata, Sharma, Gaurav, Shayani, Steven, Shirani, Jamshid, Shivaram, Pushpa, Sigman, Steven, Simon, Mitch, Slim, Ahmad, Smith, David, Smith, Alexandra, Soman, Prem, Sood, Aditya, Srichai-Parsia, Monvadi Barbara, Streeter, Jame, T, Albert, Tawakol, Ahmed, Thomas, Dustin, Thompson, Randall, Torbet, Tara, Trinidad, Desiree, Ullery, Shawn, Unzek, Samuel, Uretsky, Seth, Vallurupalli, Srikanth, Verma, Vika, Waller, Alfonso, Wang, Ellen, Ward, Parker, Weissman, Gaby, Wesbey, George, White, Kelly, Wolinsky, David, Yost, Sandra, Zgaljardic, Michael, Alonso, Omar, Beretta, Mario, Ferrando, Rodolfo, Kapitan, Miguel, Mut, Fernando, Djuraev, Omoa, Rozikhodjaeva, Gulnora, Le Ngoc, Ha, Mai, Son Hong, Nguyen, Xuan Canh, Hirschfeld, C, Shaw, L, Williams, M, Lahey, R, Villines, T, Dorbala, S, Choi, A, Shah, N, Bluemke, D, Berman, D, Blankstein, R, Ferencik, M, Narula, J, Winchester, D, Malkovskiy, E, Goebel, B, Randazzo, M, Lopez-Mattei, J, Parwani, P, Vitola, J, Cerci, R, Better, N, Raggi, P, Lu, B, Sergienko, V, Sinitsyn, V, Kudo, T, Nørgaard, B, Maurovich-Horvat, P, Cohen, Y, Pascual, T, Pynda, Y, Dondi, M, Paez, D, Einstein, A, and Erba, P

Subjects
Aging, Coronavirus disease 2019 (COVID-19), Clinical Sciences, coronavirus, Disease, 030204 cardiovascular system & hematology, Cardiorespiratory Medicine and Haematology, Cardiovascular, 030218 nuclear medicine & medical imaging, NO, 03 medical and health sciences, 0302 clinical medicine, COVID-19 Testing, Cardiovascular procedures, Predictive Value of Tests, cardiovascular disease, Clinical Research, Environmental health, INCAPS-COVID Investigators Group, Pandemic, Volume reduction, Medicine, Humans, Radiology, Nuclear Medicine and imaging, cardiovascular imaging, diagnostic cardiovascular procedure, Pandemics, business.industry, SARS-CoV-2, Prevention, COVID-19, Health Services, United States/epidemiology, United States, Invasive coronary angiography, coronaviru, Heart Disease, Good Health and Well Being, MYOCARDIAL-INFARCTION, Cardiovascular System & Hematology, Predictive value of tests, HOSPITAL ADMISSIONS, Cardiology and Cardiovascular Medicine, Early phase, business
Abstract

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection.

Published
2021

49. Carbon Quantum Dots-Based Nanozyme from Coffee Induces Cancer Cell Ferroptosis to Activate Antitumor Immunity

Author

Lu Yao, Mei-Mei Zhao, Qian-Wei Luo, Yi-Chi Zhang, Ting-Ting Liu, Zhuo Yang, Min Liao, Pengfei Tu, and Ke-Wu Zeng

Subjects
Mice, Neoplasms, Quantum Dots, General Engineering, General Physics and Astronomy, Humans, Animals, Ferroptosis, General Materials Science, Coffee, Carbon
Abstract

Carbon quantum dots (CQDs) offer huge potential due to their enzymatic properties as compared to natural enzymes. Thus, discovery of CQDs-based nanozymes with low toxicity from natural resources, especially daily food, implies a promising direction for exploring treatment strategies for human diseases. Here, we report a CQDs-based biocompatible nanozyme prepared from chlorogenic acid (ChA), a major bioactive natural product from coffee. We found that ChA CQDs exhibited obvious GSH oxidase-like activities and subsequently promoted cancer cell ferroptosis by perturbation of GPX4-catalyzed lipid repair systems. In vivo, ChA CQDs dramatically suppressed the tumor growth in HepG2-tumor-bearing mice with negligible side toxicity. Particularly, in hepatoma H22-bearing mice, ChA CQDs recruited massive tumor-infiltrating immune cells including T cells, NK cells, and macrophages, thereby converting "cold" to "hot" tumors for activating systemic antitumor immune responses. Taken together, our study suggests that natural product-derived CQDs from coffee can serve as biologically safe nanozymes for anticancer therapeutics and may aid the development of nanotechnology-based immunotherapeutic.

Published
2022

50. Dynamic Changes of Cytokine Profiles and Virological Markers Associated With HBsAg Loss During Peginterferon Alpha-2a Treatment in HBeAg-Positive Chronic Hepatitis B Patients

Author

Li, Minghui, Zhang, Luxue, Xie, Si, Sun, Fangfang, Zeng, Zhan, Deng, Wen, Jiang, Tingting, Bi, Xiaoyue, Lin, Yanjie, Yang, Liu, Lu, Yao, Shen, Ge, Liu, Ruyu, Wu, Shuling, Chang, Min, Hu, Leiping, Dong, Jianping, Yi, Wei, and Xie, Yao

Subjects
Hepatitis B Surface Antigens, Immunology, Interferon-alpha, Recombinant Proteins, Interleukin-10, Polyethylene Glycols, Hepatitis B, Chronic, DNA, Viral, Cytokines, Humans, Immunology and Allergy, Hepatitis B e Antigens, Prospective Studies, Hepatitis B Antibodies, Biomarkers
Abstract

ObjectiveTo explore dynamic changes of cytokines and virological markers associated with hepatitis B surface antigen (HBsAg) loss during peginterferon alpha-2a (PEG-IFN α-2a) treatment in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients.MethodsIt was a single-center prospective cohort study. HBeAg-positive CHB patients were prospectively and consecutively enrolled. Cytokines were detected at baseline, week 12 and 24 of PEG-IFN treatment. HBsAg disappearance rate was the primary evaluation index at 48 weeks of PEG-IFN treatment.ResultsAmong 100 patients who completed the 48-week PEG-IFN α-2a treatment, 38 patients achieved serum HBeAg disappearance, 25 patients achieved HBeAg seroconversion, 9 patients achieved functional cure, 37 patients had HBsAg decline of ≥1 log IU/ml, and 8 patients produced hepatitis B surface antibody (HBsAb). Albumin (ALB), fms-like tyrosine kinase 3 ligand (FLT3-L) and interferon-alpha2 (IFN-α2) in the clinical cure group were significantly lower than those in the non-clinical-cure group at baseline. After 12 weeks of treatment, HBsAg in the clinical cure group was significantly lower than that in the non-clinical-cure group (median 1.14 vs. 3.45 log10IU/ml, Z=-4.355, P < 0.001). The decrease of HBsAg and hepatitis B virus desoxyribose nucleic acid (HBV DNA) in the clinical cure group was significantly higher than that in non-clinical-cure group (median: HBsAg 1.96 vs. 0.33 log10IU/ml, Z=-4.703, P< 0.001; HBV DNA 4.49 vs.3.13 log10IU/ml, Z=-3.053, P=0.002). The increase of IFN-α2 in the cure group was significantly higher than that in the non-clinical-cure group (497.89 vs. 344.74, Z=-2.126, P=0.034). After 24 weeks of treatment, HBsAg, HBeAg, Flt3-L, and IL-10 in the clinical cure group were significantly lower than those in the non-clinical-cure group (median: HBsAg 0.70 vs. 3.15 log10IU/ml, Z=-4.535, P< 0.001; HBeAg 1.48 vs. 13.72 S/CO, Z = 2.512, P = 0.012; Flt3-l 0.00 vs 2.24 pg/ml, Z = 3.137, P=0.002; IL-10 0.70 vs. 2.71 pg/ml, Z=-4.067, P < 0.001). HBsAg decreased significantly in the clinical cure group compared with non-clinical-cure group (median 3.27 vs. 0.45, Z=-4.463, P < 0.001).ConclusionDynamic changes of cytokines and virology markers during early PEG IFN α-2a treatment were associated with HBsAg loss in HBeAg-positive CHB patients.

Published
2022

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